SKI (SKI proto-oncogene)

2021-02-01   Miriam Frech , Andreas Neubauer 

Clinic for Hematology, Oncology, Immunology and Center for Tumor Biology and Immunology, Philipps University Marburg, Germany \\\/ frechm@staff.uni-marburg.de, neubauer@staff.uni-marburg.de

Identity

HGNC
LOCATION
1p36.33-p36.32
ALIAS
SGS,SKV
FUSION GENES

Abstract

SKI gene is located on chromosome 1 (1p36.33-p36.32) and encodes a predominantly nuclear co-regulator of several transcription factors. SKI is also a proto-oncogene. SKI was initially found as the viral protein v-Ski of the Sloan-Kettering viruses, which are able to transform avian cells in vitro. SKI is a well described inhibitor of TGFβ signalling and is further involved in essential cellular mechanisms like proliferation and differentiation. As an oncogene SKI is further overexpressed in various tumours promoting transformation and tumour progression, but in some tumours SKI is also described as a tumour suppressor.

DNA/RNA

Atlas Image
Figure 1. Scheme of the SKI gene consisting of 7 exons. There are three MYB binding sites in exon 1 and intron 1 as well as interaction sites for serum-response factor (SRF) and PPARD in the SKI regulatory region contributing to the induction of SKI expression. Inhibition of SKI can be mediated via hypermethylation of the SKI regulatory region or micro RNAs (miRs) interacting with the 3UTR of SKI transcript.

Description

SKI is a protein coding gene that encompasses about 81.9 kb of genomic DNA and comprises 7 exons. It is located on the short arm of human chromosome 1 (1p36.33-p36.32).

Transcription

SKI has 4 transcripts of which only one is protein coding (SKI-201, ENST00000378536.5), 237 orthologues, 3 paralogues ( SKIL, SKOR1, SKOR2) and is associated with 39 phenotypes. So far only a few factors are identified, which are involved in the regulation of SKI gene expression. In murine cardiac cells, serum-response factor ( SRF) is able to interact with CArG and CArG-like boxes in the 5UTR and induces Ski expression (Zhang et al., 2005). Moreover, PPARD induces Ski expression by binding to a direct repeat-1 (DR1) response element (-865~-853) in the Ski promoter region in rat skin fibroblasts (Li et al., 2012). Also as part of a negative feedback loop, retinoic acid seems to induce SKI gene expression in Xenopus embryos and in immortalised human keratinocytes (HaCaT) (Melling et al., 2013). In human leukemic cells, SKI expression is further dependent on MYB, which interacts with MYB binding sites in the SKI regulatory region (Frech et al., 2018). It was also reported that SKI expression is inhibited by hypermethylation of the SKI promoter region in human lung cancer cells (Xie et al., 2017). Laidlaw et al. (2020) showed in a mouse model that the transcription factor Hhex induces Ski expression in memory B cells. Post-transcriptionally SKI mRNA levels are also regulated by several microRNAs (miRs), like MIR155, MIR29A, MIR21, MIR-127-3p, MIR1908, MIR17-5p, MIR34A, MIR93, MIR339 all interacting with the 3UTR (s. Figure 1).

Proteins

Note

The SKI family consists of SKI, SKIL (alias SnoN, SnoN2, SnoI, SnoA), SKOR1 (alias CORL1, FUSSEL15, LBXCOR1), SKOR2 (alias CORL2, FUSSEL18) DACH1, DACH2.

Description

SKI consists of 728 amino acids (aa) and contains three main domains. The DHD (dachshund homology domain, aa 91-192), also characterising the SKI family, is highly conserved and located near the N-terminus. It also contains Leu127, which is important for the stabilization of the DHD domain and thereby its interaction with NCOR and SMAD2 / SMAD3 (Ueki & Hayman, 2003, Wilson et al., 2004). The second conserved domain is the SAND-L (SAND-like, aa 219-312) domain. Both domains show homologies with DNA-interacting proteins but have lost the ability to bind DNA. They serve as domains for the interaction with transcription factors, transcriptional coregulators, kinases or other factors (s. Figure 2)(Bonnon & Atanasoski, 2012, Tecalco-Cruz et al., 2018). Via the interaction with other factors, SKI is recruited to the DNA and can act as co-regulator. The C-terminal part is more variable and comprises two coiled-coil (CC) regions mainly enabeling SKI homodimerization and heterodimerization with its paralog SnoN (Heyman & Stavnezer, 1994). The N-terminus further contains a proline-rich part (aa 61-89). Also, the region responsible for SKIs transformational activity lies in the N-terminal part (1-304) (Teclaco-Cruz, 2018). The degradation of SKI is regulated via PTM. For degradation via the ubiquitin-proteasome system (UPS) SKI is polyubiquitinylated at so far unidentified lysine residues by RNF111 (the E3 ligase ARKADIA). For the polyubiquitination SKI needs not only to interact with ARKADIA via aa 211-490 but also with SMAD2/3 (Nagano et al., 2007, Nagano et al., 2010). SKI is further a phosphoprotein (Struave et al., 1990). During mitosis SKI seems to be phosphorylated by CDK1 / CCNB1 (Cyclin B) and is localised at the centrososmes and mitotic spindle (Marcelain & Hayman, 2005). Furthermore, SKI phosphorylation and subsequent destabalization is mediated by the kinases AKT and AURKA. SKI phosphorylation by AKT at T458 is induced by insulin ( INS), insulin-like growth factor-1 ( IGF1R and IGF2R) and hepatocyte growth factor ( HGF) (Band et al., 2009). In contrast, AURKA phosphorylates SKI at S326 and S383 causing its degradation as well as centrosomes amplification and multipolar spindles formation (Mosquera et al, 2011, Rivas et al., 2016). S515 was described as another SKI phosphorylation site, which has no influence on SKI stability or activity. Also, the responsible kinase has not yet been identified (Nagata et al., 2010).
Atlas Image
Figure 2. SKI protein domains and interaction partners (adapted from Bonnon & Atanasoski, 2012, Tecalco-Cruz et al., 2018).

Expression

Under physiological conditions SKI is expressed at low levels in most tissues. Higher expression levels can be found in the brain, lung, male and female reproductive organs as well as bone marrow and lymphoid tissue (Human Protein Atlas v20.0 available from www.proteinatlas.org). As published in a study of Pearson-White et al. (1995), Ski is expressed in mature B and T lymphocytes as well as mature macrophages and mast cells. Further, Ski expression can be found in megakaryocyte-erythroid progenitor cells. Often mRNA levels do not correspond with protein levels (Nagano et al., 2010). Also, SKI expression was reported to be cell-cycle dependent showing the lowest protein levels in G0/G1 phase and an upregulation during mitosis (Marcelaine & Hayman, 2005). Furthermore, SKI was reported to be overexpressed in several tumor entities acting mostly oncogenic (Bonnon & Atanasoski 2012, Tecalco-Cruz et al., 2018, Liao et al., 2020).

Localisation

SKI is predominantly localised in the nucleus (Colmenares et al., 1991). The NLS consists of the sequence PRKRKLT (s. Figure 2; aa 452-458) (Nagata et al., 2006). Aberrant cytoplasmic localisation of SKI was reported in primary invasive and metastatic melanomas preventing TGFB1 -induced SMAD3 nuclear translocation (Reed et al., 2001), primary esophageal squamous cell carcinoma (Fukuchi et al., 2004), colorectal cancer (Bravou et al., 2009), Barretts esophagus (Villanacci et al., 2008) and cervical cancer (Chen et al., 2013). In hepatocytes SKI also was reported to be localised in the cytoplasm, where it co-localises with CD63- and ALIX-positive vesicles. Here, SKI stability is dependent on actin dynamics (Vázquez-Victorio et al., 2015). Cellular function seems to differ between cytoplasmic and nuclear SKI (Nagata et al., 2006). In Schwann cells SKI was reported to partially co-localise with phosphorylated RB1 in the cytoplasm affecting TGFB-induced cell proliferation (Jacob et al., 2008).

Function

SKI is a well described inhibitor of TGFβ signalling but has also influence on the associated BMP signalling and other cellular pathways relevant for cancer development including nuclear hormone receptor signalling, Sonic hedgehog ( SHH) signalling, Hippo signalling, PI3K/Akt signalling and Wnt/β-catenin signalling (Bonnon & Atanasoski, 2012, Liao et al., 2020). SKI acts as a corepressor for SMAD proteins thereby inhibiting TGFβ signalling. Via the interaction with SMAD complexes SKI blocks the interaction with co-activator molecules like EP300 (CBP/P300) and additionally recruits co-repressor complexes to SMAD target genes (Luo et al., 1999, Akiyoshi et al., 1999). SKI is also able to suppress BMP signalling via weak interactions with BMP-specific SMAD complexes and inhibition of BMP target gene expression by interacting with homologous domain interaction protein kinase 2 ( HIPK2) (Wang et al., 2000, Takeda et al., 2004, Harada et al., 2003). The presence of SKI is also needed for the inhibition of nuclear hormone receptor signalling. SKI is an essential part of the NCOR1 / NCOR2, SIN3A and HDAC-recruiting co-repressor complex and contributes to the inhibition of thyroid hormone receptors ( THRA and THRB), RARA and VDR signalling (Nomura et al., 1999, Dahl et al., 1998, Ritter et al., 2006, Ueki & Hayman, 2003). SKI further is involved in the inhibition of SHH signalling by binding to GLI3 protein and recruiting HDAC1 to SHH-induced genes like GLI1 (Dai et al., 2002). In contrast, in pancreatic cancer cells SKI was reported to augment pluripotency of pancreatic cancer stem cells via induction of SHH signalling (Song et al., 2016). SKI can also act as a tumor suppressor and was reported to inhibit breast and lung cancer progression via blocking Hippo/TAZ signalling by increasing TAZ phosphorylation or recruiting co-repressors to TAZ (Rashidian et al., 2015, Xie et al., 2017). SKI is not only a repressor but also activates certain pathways. It was published by Zhao et al. (2020) that SKI knockdown in osteosarcoma (OS) cells causes dephosphorylation of PI3K and AKT leading to decreased OS cell proliferation and migration. Furthermore, in melanoma cells SKI together with FHL2 promotes Wnt/β-catenin signalling and induces the expression of the tumorigenic genes MITF and NRCAM (Chen et al., 2003). In colorectal cancer SKI also significantly correlates with Wnt/β-catenin signalling (Bravou et al., 2009).
SKI interacts with several PU.1 different factors (s. Figure 2) and functions as a co-regulator. SKI was reported to inhibit i.a. GATA1 (Ueki et al., 2004), SPI1 (PU.1) (Ueki et al., 2008), TP53, together with SIRT1 or via MDM2 sumoylation, (Inoue et al., 2011, Ding et al., 2012) and RUNX1 (Feld et al., 2018). It also acts as a co-activator for factors like nuclear factor I (NFI) (Tarapore et al., 1997) or MYOD1, SIX1 and EYA3 during myogenesis (Kobayashi et al., 2007, Zhang & Stavnezer, 2009).
As in mature tissues, also during murine embryonic development low levels of SKI are expressed in most tissues. Highest expression levels can be found in brain and lung (Lyons et al., 1994, Namciu et al., 1995). SKI is crucial for the neuronal development, myogenesis and limb formation. In murine models, SKI downregulation causes aberrant neural tube closure leading to exencephaly, aberrant craniofacial, ocular, skeletal and muscle development (Berk et al., 1997, McGannon et al., 2006, Shinagawa and Ishii, 2003, Colmenares et al., 2002). SKI is further involved in the myelination of Schwann cells (Atanasoski et al., 2004). Even though SKI is relevant for myogenesis, it was reported that ectopic expression of SKI causes hypertrophy of fast skeletal muscle fibers (Lana et al., 1996, Leferovich et al., 1995, Sutrave et al., 1990, 2000). In humans SKI also may be relevant for neuronal and craniofacial development, since patients with the 1p36 deletion syndrome show similar symptoms like mice with a Ski deletion including developmental delay, orofacial clefting and congenital heart defects (Colmenares et al., 2002, Jordan et al., 2015). Moreover, SKI plays a role in hematopoietic differentiation (Namciu et al., 1994, Pearson-White et al., 1995, Dahl et al., 1998, Ueki et al., 2004, 2008, Singbrandt et al., 2014 Zhang et al., 2017). SKI is overexpressed in memory B cells (MBCs) and induces cell proliferation and differentiation (Bhattacharya et al., 2007, Laidlaw et al., 2020). Moreover, SKI is higher expressed in actively maintained quiescent tumour-infiltrating CD8+ T cells from liver tumours compared to natural quiescent T cells from the peripheral blood (Zhang et al., 2009). SKI is upregulated via T cell integrin leukocyte function-associated antigen-1(LFA-1) interacting with ICAM1 in T cells. Consequentially, SKI contributes to the inhibition of the TGFβ-mediated T cell quiescent state (Verma et al., 2012). In a mouse model, Ski inhibits CD103 (Itgae) expression in CD8+ T cells via histone hypoacetylation. This mechanism is dependent on SMAD4. The suppression of CD103+CD8+ T cell generation further leads to a higher susceptibility to secondary viral infections (Wu et al., 2020). In T cells, SKI and SMAD inhibit IL21 -induced differentiation into T helper 17 cells (Th17) via suppressing retinoic acid receptor-related orphan receptor γt (RORγt) expression (Zhang et al., 2017, 2019). SKI affects fibroblastic proliferation and development (Jinnin et al., 2007, Liu et al., 2008, Cunnington et al., 2011) and induces chondrocytic differentiation via inhibition of TGFβ signalling (Kim et al., 2012). The expression of SKI alters under many pathological conditions including demyelination or peripheral nerve damage (Atanasoski et al., 2004), wound healing (Liu et al., 2006, 2010, Li et al., 2011), liver regeneration (Macias-Silva et al., 2002), skeletal muscle regeneration (Soeta et al., 2001) and obstructive nephropathy (Fukasawa et al., 2006).

Homology

SKI homologues have been identified in vertebrates from fish to human.

Mutations

Note

Several coding and non-coding sequence variants of SKI were identified, also containing one coding non-synonymous variant, rs28384811 (White et al., 2008).
In patients with Shprintzen-Goldberg syndrome (SGS) mutations in exon 1 of SKI are responsible for ~90 % of the cases. The mutations can be found in the SMAD interaction domain and DHD domain resulting in the substitution or deletion of amino acids and leading to the induction of TGFβ signalling (Doyle et al., 2012, Carmignac et al., 2012, Au et al., 2014, Schepers et al., 2015, Polinska et al., 2016, Saito et al., 2017). However, it was proposed that during embryogenesis SKI mutations in the SMAD interaction domain or DHD domain effect TGFβ signalling differently, since a patient carrying a mutation in the SKI DHD domain developed lipomeningomyelocele, tethered cord and spina bifida but no SGS characteristics like intellectual disability, craniofacial or cardiovascular abnormalities (Zhang et al., 2019). Also, another mutation in the SKI DHD domain affecting the amino acid Thr180 was reported to be associated with marfanoid syndrome with thoracic aortic aneurysm but no intellectual disability (Arnaud et al., 2020).
A small deletion (576 kb) of 1p36.33-p36.32 encompassing SKI was found in a patient with limb malformations, congenital heart disease (CHD), epilepsy and mild development delay (Zhu et al., 2013).
In a paediatric case of de novo acute myeloid leukaemia with del(5q) a SKI out-of-frame fusion transcript with PRDM16, PRDM16(exon 1)/SKI(exon 2) t(1;1)(p36;p36) PRDM16/SKI, was identified together with another translocation, RUNX1(exon 6)/ USP42 (exon 3) t(7;21)(p22;q22) RUNX1/USP42 (Masetti et al., 2014).
SKI mutationAA changedomainWhite et al. (2008)Doyle et al. (2012)Carmignac et al. (2012)Au et al. (2014)Schepers et al. (2014)Poninska et al. (2016)Saito et al. (2017)Zhang et al. (2019)Arnaud et al. (2020)Total
c.59C>Gp.Thr20ArgSMAD      1  1
c.59C>Ap.Thr20LysSMAD     1   1
c.62T>Gp.Leu21ArgSMAD 1       1
c.82T>Ap.Ser28ThrSMAD    1    1
c.92C>Tp.Ser31LeuSMAD  1 1    2
c.94C>Gp.Leu32ValSMAD 2*3* 1    5*
c.95T>Cp.Leu32ProSMAD  1      1
c.100G>Ap.Gly34SerSMAD 11 1    3
c.100G>Tp.Gly34CysSMAD 11      2
c.101G>Ap.Gly34AspSMAD 1  1    2
c.101G>Tp.Gly34ValSMAD  1 1    2
c.101G>Cp.Gly34AlaSMAD    1    1
c.103C>Tp.Pro35SerSMAD 1112    5
c.104C>Ap.Pro35GlnSMAD  1      1
c.185C>Gp.Ala62GlySMAD3        3
c.280_291delp.Ser94_Ser97delDHD  1      1
c.283_291delp.Asp95_Ser97delDHD 11      2
c.289_300delp.Ser97_Arg100delDHD    1    1
c.336C>Gp.Cys112TrpDHD       1 1
c.347G>Ap.Gly116GluDHD 1 1     2
c.349G>Cp.Gly117ArgDHD 1       1
c.539C>Tp.Thr180MetDHD        55
c.539C>Ap.Thr180LysDHD        22
c.539C>Gp.Thr180ArgDHD        22
   389210111948

*one common patient
Table1. Overview of the published SKI mutations leading to AA changes or deletions (adapted from Schepers et al., 2015, Arnaud et al., 2020).

Implicated in

Entity name
Shprintzen-Goldberg Syndrome
Note
Variations and mutations of SKI exon 1 cause ~90 % of the cases with Shprintzen-Goldberg syndrome (SGS). (see also section Mutations and Table 1).
Entity name
1p36 Deletion Syndrome
Note
1p36 is the most common subtelomeric deletion syndrome and occurs in ~1 out of 5,000 cases (Heilstedt et al., 2003). SKI is one of the genes deleted in 1p36 deletion syndrome contributing to certain aspects of the disease. Also, SKI-deficient mice recapitulate aspects of the 1p36 deletion syndrome (Colmenares et al., 2002). Some but not all characteristics of 1p36 deletion syndrome overlap with Shprintzen-Goldberg syndrome like developmental delay, intellectual disability and a high, narrow palate. The differences were reported to be possibly due to the creation of loss-of-function alleles by the SKI mutations in 1p36 deletion syndrome but not in Shprintzen-Goldberg syndrome. In 1p36 deletion syndrome, deletion of SKI is supposed to contribute to developmental delay, intellectual disability, seizures, orofacial clefting and congenital heart defects (Jordan et al., 2015). In the development of cardiomyopathy, insufficiency of SKI and PRDM16, a gene also deleted in 1p36 deletion syndrome, may cooperate (Rosenfeld et al., 2010, Zaveri et al., 2014). Contrarily, it was published recently that not PRDM16 but the deletion of SKI and the congenital heart disease-associated genes RERE and UBE4B are the causing factors for Ebstein anomaly (EA) in 1p36 deletion syndrome patients (Miranda-Fernández et al., 2018).
Entity name
Cardiac Fibrosis
Note
TGFβ induces cardiac fibrogenesis. Via inhibiting TGFβ signalling, SKI is able to inhibit cardiac fibrosis. Expression of SKI decreases the myofibroblast phenotype including reduced contractility, possibly by a decreased expression of α-smooth muscle actin (α-SMA: ACTA2) and less type I collagen secretion. SKI-induced decrease of myofibroblasts may be due to a redifferentiation to fibroblasts via SKI-induced repression of ZEB2 and reexpression of MEOX2 and/or inhibition of autophagy and induction of apoptosis (Cunnington et al., 2011, 2014, Zeglinski et al., 2016). Vice versa, ARKADIA induces SKI and SMAD7 degradation and thereby contributes to cardiac fibrosis (Cunnington et al., 2009). In diabetes, myocardial infarction can lead to cardiac fibrosis. Here, MIR155 is upregulated leading to SKI inhibition. PBMC transplantation causes the release of hepatocyte growth factor (HGF), which acts antifibrotic via inhibiting MIR155 and inducing SKI (Kishore et al., 2013). Besides MIR155 also MIR17, MIR34A and MIR93 inhibit SKI and contribute to development of cardiac fibrosis by inducing TGFβ signalling, cardiac fibroblast proliferation and extracellular matrix protein production (Wang et al., 2017, Zhang et al., 2018). The MIR155/SKI axis further plays a role in fibrogenic endothelial-mesenchymal transition (EndMT) of human coronary artery endothelial cells (HCAEC), which also supports cardiac fibrosis. Depletion of MIR155 reestablishes SKI expression leading to the downregulation of VIM (Vimentin), SNAI1, SNAI2 (Slug) and TWIST1 as well as the induction of PECAM1 (CD31) and in the end to the inhibition of EndMT (Wang et al., 2017). Downregulation of SKI in cardiac muscle cells also supports TGFβ-induced epithelial-mesenchymal transitions via inhibition of CDH1 (E-cadherin) and induction of ACTA2 and/or FN as well as SMAD3 phosphorylation (Ling et al., 2019). In myofibroblasts, SKI further induces MMP9 expression and associated gelatinase activity, which may enable cytoskeletal remodelling and may have an effect on extracellular matrix components (Landry et al., 2018).
Entity name
Haemangioma
Note
SKI is overexpressed in haemangiomas, as shown in a study with 12 patients. SKI levels are high in actively proliferating haemangioma cells and lower in involuting haemangiomas (O et al., 2009).
Entity name
Myelodysplastic Syndrome (MDS)
Note
Muench et al. (2018) showed that SKI protein is inhibited by elevated MIR21 expression in early stage MDS, supporting chronic induction of TGFβ signalling and deregulation of splicing factors. Moreover, SKI is crucial for hematopoietic stem cell (HSC) fitness, involving inhibition of TGFβ signalling and aberrant RNA splicing in mice.
Entity name
Note
In tumorigenic diseases SKI is rather overexpressed than mutated. Nevertheless, a PRDM16/SKI out-of-frame translocation was reported in a paediatric case of del(5q) AML, which is predicted not to be translated but to increase PRDM16 expression, which is already associated with leukemogenesis (Masetti et al., 2014).
Compared with CD34-positive stem cells of healthy donors, SKI is overexpressed in different acute myeloid leukaemia (AML) subgroups (Ritter et al., 2006). Overexpression of SKI in-7/del7q AML patients is due to deletion of the SKI-targeting MIR29A, encoded on chromosome 7q (Ritter et al., 2006, Teichler et al., 2011). Recently it was published that the oncogenic long non-coding RNA LINC00467 is upregulated and contributes to the AML phenotype. Downregulation of LINC00467 induces MIR339 expression and inhibition of the MIR337 target SKI (Lu et al., 2020). In AML, SKI expression is further dependent on the oncogenic haematopoietic transcription factor MYB and contributes to its inhibitory activity in myeloid differentiation (Frech et al., 2018). In avian bone marrow, Ski increases stem cell-ness of primary multipotential progenitor cells, what may be relevant for leukemogenesis (Beug et al., 1995). In a mouse model exogenous expression of Ski in hematopoietic stem and progenitor cells induces a stem cell gene expression signature and causes the development of a myeloproliferative disorder in vivo. Here, SKI-positive myeloid progenitor cells seem to depend on HGF signalling (cf. Kishore et al., 2013) but not on the inhibition of TGFβ signalling (Singbrant et al., 2014). SKI as part of the co-repressor complex was reported to interact with the nuclear body protein PML and may be involved in PML/RARα-inducedacute promyelocytic leukaemia (APL) (Khan et al., 2001). SKI contributes to the development of erythroleukemia via interacting with the erythroid transcription factor GATA1. SKI promotes erythroblastic proliferation and blocks GATA1 DNA binding ability, causing an erythroid differentiation block (Larsen et al., 1992, Ueki et al., 2004, Fagnan et al., 2020). A regulatory mechanism of SKI with the histone methyltransferase nuclear receptor SET domain protein 1 ( NSD1) may also play a role in erythroleukemia (Leonards et al., 2020). SKI may further contribute to leukemogenesis via blocking activity of the important hematopoietic transcription factor PU.1 by recruiting an HDAC3 -containing co-repressor complex to its target genes (Ueki et al., 2008). In AML, SKI inhibits the signalling pathway of the important retinoic acid receptor α (RARα) crucial for myeloid differentiation via interacting with the HDAC-recruiting NCOR co-repressor complex. The differentiation block can partially be released with the HDAC inhibitor valproic acid (Dahl et al., 1998, Ritter et al., 2006). SKI also seems to block RARα signalling and the response to all-trans retinoic acid (ATRA) treatment in AML patients, also treated with chemotherapy, in vivo (Teichler et al., 2008). Feld et al. (2018) further analysed the SKI-dependent cistrome and transcriptome in AML cells and showed that SKI blocks myeloid differentiation and acts as a co-repressor for the haematopoietic transcription factor RUNX1.
Note
SKI is upregulated in CD34-positive cells of patients with chronic myelogenous leukemia (CML) (n=5) compared to CD34-positive cells of healthy donors (n=10) (Kronenwett et al., 2005).
Entity name
Chronic Lymphocytic Leukemia (CLL)
Note
SKI and SLAMF1 may be prognostic in CLL. In previously untreated CLL patients (n=133), a higher expression of SKI and SLAMF1 is associated with a longer time-to-treatment (Schweighofer et al., 2011).
Entity name
Melanoma
Note
SKI is overexpressed in melanoma cell lines (Fumagalli et al., 1993) as well as in melanoma patients as shown by Reed et al. (2001, n=44) and Boone et al. (2009, n=120). In melanoma, SKI overexpression may be due to a downregulation of MIR155. Nevertheless, the inhibition of SKI is not the main cause for the MIR155-mediated suppression of proliferation and induction of apoptosis in melanoma cells (Levati et al., 2011). Furthermore, SKI expression is up-regulated by MAPK/ERK signalling, while a MEK inhibitor decreases SKI levels (Rothammer & Bosserhoff, 2006). SKI was further reported to increase cell cycle progression by inhibiting Smad-mediated induction of CDKN1A ("p21Waf-1"), thereby increasing CDK2 activity. SKI overexpression induces RB1 inactivation and increases colony size and formation in human melanoma cells (Medrano, 2003). The inhibition of TGFβ signalling by SKI also contributes to tumour growth and angiogenesis via increasing the level of oncogenic MYC and inducing expression of SERPINE1 (PAI-1) in melanoma cells (Reed et al., 2001, Chen et al., 2009). SKI also augments melanoma cell growth via acting as a co-activator for FHL2 and β-catenin to induce Wnt signalling. It thereby induces the expression of MITF and NRCAM, which are already associated with cell transformation, survival, growth and motility in melanoma (Chen et al., 2003). In primary invasive melanoma cells, SKI was predominantly found in the nucleus. In metastatic cells, SKI rather localises to the cytoplasm (Reed et al., 2001, Javelaud et al., 2011). Nuclear SKI was also found in ulcerated tumours but not in metastatic melanoma cells. Also, nuclear SKI is positively correlated with Breslow thickness (Boone et al., 2009). The role of SKI with melanoma malignancy is still under discussion. While Reed et al. (2001) showed that increased SKI levels correlate with increased melanoma malignancy, Boone et al. (2009) found no correlation of SKI levels with tumour progression, histogenetic subtype or patient survival. In mice, Javelaud et al. (2011) found Ski not to be correlated with melanoma cell growth or metastasis. Here, Ski levels even decreased upon treatment with increasing amounts of TGFβ.
Entity name
Osteosarcoma
Note
Zhao et al. (2020) published that SKI is overexpressed in osteosarcoma cell lines. SKI knockdown inhibited PI3K/AKT signalling as well as cell proliferation and migration of the cell lines. Moreover, increased SKI levels were detected in patients with osteosarcoma (n=6) compared to osteochondroma tissue (n=6). The patients were not treated with radiotherapy or chemotherapy before surgery.
Entity name
Lung Cancer
Note
In lung cancer, SKI rather acts as a tumour suppressor. SKI knockdown in lung cancer cells increases metastasis in a mouse model in vivo (Le Scolan et al., 2008). In turn, SKI overexpression inhibits TGFβ signalling in lung cancer cell lines, including translocation of SMAD2 to the nucleus and SMAD3 phosphorylation (Ferrand et al., 2010, Yang et al., 2015). Moreover, Makino et al. (2017) published that together with IL6 and STAT3, SKI may also mediate gefitinib drug resistance of lung cancer cells caused by inflammatory processes. Gefitinib is a tyrosin kinase inhibitor used for treatment of lung cancer with EGFR mutation. The proinflammatory cytokine IL6 induces STAT3 phosphorylation and STAT3 interacts with SKI and SKIL to inhibit TGFβ signalling and SMAD3 expression. Inhibition of SMAD3 expression inhibits gefitinib-induced apoptosis (Makino et al., 2017). SKI overexpression further inhibits epithelial-mesenchymal transition induced by TGFβ signalling (Yang et al., 2015). Yang et al. (2015) showed lower SKI transcript levels in metastatic (n=23) non-small lung cancer cells (NSCLCs) compared with non-metastatic (n=23) NSCLCs of lung cancer patients. The patients were not treated with radiotherapy or chemotherapy before sampling. Moreover, Xie et al. (2017) showed that a higher SKI expression in lung cancer is associated with a longer overall survival. In lung cancer cells, SKI is predominantly localised to the cytoplasm. Also, SKI is lower expressed in primary lung cancer tissues (n=168) compared to adjacent normal lung tissues (n=20). This is due to an increased SKI DNA methylation pattern in lung cancer cells. Treatment of the lung cancer cells with the methyltransferase inhibitor 5-aza-2-deoxycytidine (decitabine) reestablishes SKI expression. In lung cancer patients, SKI expression is positively correlated with differentiation and negatively associated with tumour stage. As in breast cancer cells (see below), SKI inhibits TGFβ-induced SMAD and TAZ signalling in lung cancer cell lines. TAZ inhibition by SKI suppresses growth, colony formation, migration and invasion of lung cancer cell lines (Xie et al., 2017).
Entity name
Gastric Cancer
Note
In gastric cancer cells, SKI and another co-regulator PRDM16 (former MEL1) are co-amplified (Takahata et al., 2009). Both genes are encoded on chromosome 1p36, a locus which was reported to have an increased copy number in 22 % of gastric cancers (Sakakura et al., 1999). PRDM16 interacts with SKI and stabilises the SKI/SMAD3 complex, thereby inhibiting TGFβ target gene expression and inducing cell proliferation. In a mouse model, knockdown of Ski and Prdm16 in gastric tumour cells reduces tumour growth in vivo (Takahata et al., 2009). Vice versa, overexpression of SKI in diffuse-type gastric cancer cells inhibits TGFβ expression as well as signalling and induces tumour growth in a xenograft mouse model. SKI overexpression further leads to less fibrosis and inhibits expression of anti-angiogenic thrombospondin 1 ( THBS1), thereby promoting tumour angiogenesis (Kiyono et al., 2009). In contrast, Nakao et al. (2011) showed that THBS1 and SKI level are not associated in patients with advanced gastric cancer. Moreover, THBS1 expression correlates with increased angiogenesis and a better survival in advanced gastric cancer patients, while SKI expression is associated with a poorer survival in TGFβ-positive patients (Nakao et al., 2011). SKI is upregulated in gastric cancer patients tissue and gastric cancer cell lines. Increased expression of SKI in gastric cancer-associated fibroblasts (CAFs) enhances cell viability, cell invasion and cell migration, probably by inhibiting SMAD3 activity in TGFβ signalling. SKI knockdown in CAFs reverses these effects (Zhang et al., 2019).
Entity name
Pancreatic Cancer
Note
In pancreatic cancer, SKI is frequently overexpressed and was published to act as a proto-oncogene but also as a tumour suppressor. SKI knockdown in pancreatic cancer cells leads to reactivation of SMAD2/3-mediated TGFβ signalling and inhibition of tumour growth in mice, but to induction of metastasis to the lung (Heider et al., 2007, Wang et al., 2009). SKI is associated with a shorter overall survival in patients with pancreatic ductal adenocarcinoma (PDAC) (Wang et al., 2009). SKI overexpression further increases pluripotency of pancreatic cancer stem cells via activation of SHH signalling. In vitro and in an in vivo mouse model, SKI knockdown leads to a reduction of factors involved in stem cell maintenance ( CD24, CD44, POU5F1 (former OCT-4), SOX2) and SHH signalling (SHH, PTCH1, SMO, GLI1, GLI2, while SKI overexpression shows the reverse effects (Song et al., 2016). Ponath et al. (2020) showed that SKI suppresses NK cell-mediated killing of pancreatic cancer cells, probably by inhibiting the basal as well as HADCi-induced expression of KLRK1 (NKG2D) ligands.
Entity name
Colorectal Cancer
Note
In early-stage colorectal cancer patients (n=159), SKI is overexpressed. Allelic amplification (10.1%) but not allelic loss (41.5%) of SKI is associated with a shorter disease-free survival and overall survival (Buess et al., 2004). Another analysis of 70 primary human colorectal adenomas/carcinomas (CRCs) as well as 21 lymph node metastases showed SKI overexpression in 75.7% or 71.4% of the cases, respectively. No or only weak SKI levels were detected in normal colon mucosa. In CRCs, SKI is predominantly localised in the cytoplasm and correlates with β-Catenin signalling (Bravou et al., 2009).
Entity name
Oesophageal Squamous Cell Carcinoma
Note
SKI is overexpressed in oesophageal squamous cell carcinoma cell lines and patient cells (56.3%, n=80). Expression of SKI is correlated with invasion depth, tumour stage and a shorter overall survival after surgery in patients with TGFβ-negative tumours. SKI level further correlate with TGFβ and CDKN1A (P21) expression (Fukuchi et al., 2004).
Entity name
Barretts oesophagus
Note
Evaluation of 37 patients with Barrets oesophagus (BE) show an overexpression of SKI in BE and a lower expression in BE with low-grade dysplasia, but no expression in normal oesophageal tissue and BE with high-grade dysplasia/adenocarcinoma. In BE, SKI may be involved in the suppression of TGFβ-mediated growth inhibition (Villanacci et al., 2008).
Entity name
Kidney Cancer
Note
SKI is higher expressed in clear cell renal carcinoma (ccRCC) (n=31) compared to normal renal tissue of the same patients and localises to the nucleus. Overexpression of SKI in a mouse renal orthotopic tumour model inhibits TGFβ signalling as well as the TGFβ-associated growth inhibition and increases tumour growth in vivo (Taguchi et al., 2019).
Entity name
Breast Cancer
Note
In breast cancer, SKI was published to act more as a tumour suppressor than a proto-oncogene. SKI overexpression inhibits breast cancer metastasis to lung and liver in a mouse model. This is dependent on the inhibition of TGFβ signalling by SKI (Azuma et al., 2005). Vice versa, SKI knockdown in a human breast cancer cell line augments metastasis in mice. Also, TGFβ treatment of these cells leads to a decrease of SKI protein levels (Le Scolan et al., 2008). However, SKI overexpression inhibits TGFβ-induced nuclear translocation of SMAD2 in the same breast cancer cell line (MDA-MB231) (Ferrand et al., 2010). Theohari et al. (2012) further analysed 119 patients with resectable invasive breast cancer and showed that SKI is localised in the cytoplasm (44.5%) and the nucleus (17.6%). Cytoplasmic SKI is inversely correlated with tumour size, stage and status of the lymph nodes and nuclear SKI is negatively associated with histological grade and nuclear phosphorylated SMAD2. Cytoplasmic SKI is further related to a longer overall survival and disease-free survival (Theohari et al., 2012). In breast cancer cell lines, SKI also activates the Hippo signalling-associated kinase LATS2, which leads to the phosphorylation and degradation of TAZ. TAZ signalling is associated with breast cancer progression. SKI also inhibits TAZ/TEAD target gene expression by recruitment of NCOR1 and induces TAZ degradation via a LATS2-independent mechanism. Furthermore, SKI suppresses TAZ-induced transformation and epithelial-mesenchymal transition in vitro as well as lung metastases in mice in vivo (Rashidian et al., 2015). A proto-oncogenic function of SKI in breast cancer progression was published by Wang et al. (2013). Here, SKI was described to be overexpressed in breast cancer-associated fibroblasts (CAFs) in the tumour microenvironment contributing to invasion and metastasis of breast cancer cells. SKI overexpression in normal fibroblasts induces transformation to CAFs with increased proliferation, migration, invasion and contraction.
Entity name
Cervical Cancer
Note
In association with human papillomavirus (HPV)-derived cervical cancer, it was published that SKI and NFI cooperate in the induction of HPV16 early gene expression. A decrease of HPV16 early gene expression by TGFβ is accompanied by a reduction of SKI levels and suppressed NFI activity (Baldwin et al., 2004). Further studies showed that SKI is higher expressed in cervical cancer samples (n=42) compared to adjacent normal cervix tissue (n=38). In contrast to normal cervical tissue, where SKI is localised to the nuclei and less to the cytoplasm, in cervical cancer tissue SKI was predominantly localised to the cytoplasm. Moreover, SKI level increase during transformation of human keratinocytes immortalised with HPV16 DNA (HKc/HPV16), with highest levels in differentiation-resistant HKc/HPV16 (HKc/DR), which are also resistant to growth inhibition by TGFβ. Knockdown of SKI in HKc/DR further leads to a decrease in cell proliferation (Chen et al., 2013).
Entity name
Prostate Cancer
Note
Vo et al. (2012) showed that SKI is overexpressed in prostate cancer cell lines and inhibits TGFβ signalling. Contrarily, SKI level were low to not detectable in prostate stem cells and normal prostate cell lines. In prostate cancer cell lines, SKI knockdown inhibits cell proliferation but increases cell migration. Also, patients with prostate adenocarcinomas and metastatic prostate cancer show a SKI overexpression, while SKI is not detectable in normal prostate tissues. In prostate cancer, localisation of SKI is predominantly cytoplasmic.

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Other Information

Locus ID:

NCBI: 6497
MIM: 164780
HGNC: 10896
Ensembl: ENSG00000157933

Variants:

dbSNP: 6497
ClinVar: 6497
TCGA: ENSG00000157933
COSMIC: SKI

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000157933ENST00000378536P12755

Expression (GTEx)

0
50
100
150
200
250

Pathways

PathwaySourceExternal ID
Signal TransductionREACTOMER-HSA-162582
Signaling by BMPREACTOMER-HSA-201451
Signaling by TGF-beta Receptor ComplexREACTOMER-HSA-170834
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimerREACTOMER-HSA-2173793
Downregulation of SMAD2/3:SMAD4 transcriptional activityREACTOMER-HSA-2173795
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
230233322012Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm.74
163278842005Medical sequencing of candidate genes for nonsyndromic cleft lip and palate.70
124192462002Structural mechanism of Smad4 recognition by the nuclear oncoprotein Ski: insights on Ski-mediated repression of TGF-beta signaling.61
184511542008Transforming growth factor-beta suppresses the ability of Ski to inhibit tumor metastasis by inducing its degradation.44
127641352003The transforming activity of Ski and SnoN is dependent on their ability to repress the activity of Smad proteins.38
190499802009SKI and MEL1 cooperate to inhibit transforming growth factor-beta signal in gastric cancer cells.32
145834552003SKI activates Wnt/beta-catenin signaling in human melanoma.31
151078212004c-Ski inhibits the TGF-beta signaling pathway through stabilization of inactive Smad complexes on Smad-binding elements.29
190323432009Ski co-repressor complexes maintain the basal repressed state of the TGF-beta target gene, SMAD7, via HDAC3 and PRMT5.28
128742722003Requirement of the co-repressor homeodomain-interacting protein kinase 2 for ski-mediated inhibition of bone morphogenetic protein-induced transcriptional activation.24

Citation

Miriam Frech ; Andreas Neubauer

SKI (SKI proto-oncogene)

Atlas Genet Cytogenet Oncol Haematol. 2021-02-01

Online version: http://atlasgeneticsoncology.org/gene/42303/ski-(ski-proto-oncogene)