Note | Molecular weight: NP_060296.2 ~46.9 kDa, 425aa; NP_001269076.1 ~25.1 kDa, 225 aa |
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| Figure 1 - Schematic representation of the human SOHLH2 protein SOHLH2 is a 425aa protein with one basic helix-loop-helix DNA-binding motif (bHLH, 197-257aa) |
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Description | SOHLH2 is a ~46.9 kDa protein (initially described as a 51kDa (Ballow et al., 2006)), composed of 425 amino acids, with an isoelectric point of 7.1377. SOHLH2 has a basic helix-loop-helix DNA-binding (bHLH) motif of 60aa (197-257aa) thus it has being described as a transcription factor (figure 1). The amino-terminal portion of bHLH corresponds to the basic domain, enabling the binding of the protein to its consensus sequence at the DNA, known as E-Box. The HLH portion is at the carboxy-terminal portion of bHLH and is a structure covering two α -helices connected by a loop which is responsible for the interactions with other protein subunits to form homo- and heterodimeric complexes (Jones, 2004; Gyoja, 2017). |
Expression | SOHLH2 protein expression is observed in the nuclei of oocytes, and weak staining is present in the cytoplasm of theca cells and granular cells in the ovary. The SOHLH2 transcripts expression are detectable specifically in the oocytes of small follicles of female embryonic gonad. In adult ovaries, SOHLH2 protein is present in primordial follicles and absent in growing oocytes (Ballow et al., 2006). In testis, SOHLH2 is found mainly in spermatogonia and Sertoli cells in seminiferous tubule and Leydig cells outside of seminiferous tubules (Ballow et al., 2006; Zhang et al., 2015). Although SOHLH2 has been initially described in testis and oocytes, it is widely expressed in normal adult human tissues. The expression of SOHLH2 is also observed in the cytoplasm of the three kinds of muscle tissues: skeletal, cardiac and smooth. SOHLH2 protein expression was also found in other tissues derived from embryonic mesoderm such as kidney and uterine tube (Zhang et al., 2015). In neurons, Sohlh2 were detected mainly in the nuclei, while it was not detectable by IHC in neuroglial cells. The expression of SOHLH2 gene was also detected in some other tissues derived from embryonic ectoderm including iris, ciliary body, and retina (Zhang et al., 2015). |
Localisation | SOHLH2 is an intracellular protein present predominantly in the nucleus but also in the cytoplasm of specific cell types (Zhang et al., 2015; Shin et al., 2017). Its translocation from the cytoplasm is associated with expression of SOHLH1 (Shin et al., 2017). |
Function | Tissue-specific basic helix-loop-helix (bHLH) transcription factors play critical roles in cell differentiation SOHLH2 is described as a transcription regulator of both male and female germline differentiation. SOHLH2, together with SOHLH1, regulates oocyte growth and differentiation (Shin et al., 2017). SOHLH proteins modulate the expression of genes involved in spermatogonial stem cells maintenance (SSC), such as RET, GFRA1, NANOS2, and POU5F1. Also, it regulates the expression of genes essential for spermatogonial differentiation such as KIT, and SOX3 (Suzuki et al., 2012). According to Toyoda et al. SOHLH2 forms a ternary complex with SOHLH1, and SP1 and cooperatively regulates the transcription of SOHLH1 gene (Toyoda et al., 2014). |
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| Figure 2 - Schematic representation of the mechanism of action of SOHLH2. SOHLH2 negatively regulates cell proliferation trough upregulation of APC expression and inhibition of Wnt/βcatenin signaling and suppresses migration and invasion by down-regulation of IL-8. SOHLH2 - spermatogenesis and oogenesis specific basic helix-loop-helix 2; APC - adenomatosis polyposis coli/APC regulator of WNT signaling pathway; IL-8 - Interleukin 8 (Zhang et al., 2016; Ji et al, 2016) |
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Homology | Although SOHLH2 was identified as a homologue of SOHLH1, their limited homology is confined to the bHLH domains (~50%) (Suzuki et al., 2012). The bHLH protein domain of SOHLH2 is the most conserved region among different species (Ballow et al., 2006). The described identity among mouse SOHLH2 protein with the rat and human orthologue is 84% and 50%, respectively (Ballow et al., 2006). |
Note | SOHLH2 is a transcription regulator involved in spermatogenesis and oogenesis, but also in Cancer: Basic helix-loop-helix (bHLH) proteins play several roles in tumorigenesis, such as cell differentiation, cell cycle arrest and apoptosis (Sun et al., 2007). |
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Entity | Spermatogenesis and Azoospermia |
Note | Spermatogenesis is a process by which male gametes, known as sperm, are formed from primordial germ cells (spermatogonia). Hao et al. (2008) have observed that mice null for Sohlh2 (Sohlh2 -/-) showed testis with a significantly diminished size. Moreover, based on testicular atrophy, functional studies have shown that type A spermatogonia differentiation was interrupted in SOHLH2 null mice (Hao et al., 2008). Azoospermia is a condition characterized by the absence of sperm cells in the semen, classified into two groups: obstructive azoospermia (OA) and non-obstructive azoospermia (NOA). In a Chinese study evolving a cohort of 361 of patients, Song et al. have described two variants, with different risk impact of NOA development. The rs6563386 variant conferred a higher risk of NOA while the rs1328626 variant was associated with lower risk of NOA, suggesting a direct relation of SOHLH2 gene to NOA development (Song et al., 2015). |
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Entity | Premature Ovarian Failure |
Note | The Premature Ovarian Failure (POF), sometimes referred to as Premature Menopause, is a human female gonadal failure before forty years old. Eleven variants of SOHLH2 were described in a series of 561 POF patients, suggesting that this gene might play a role in human POF etiology (Qin et al., 2014). In another work, the association of SOHLH2 with POF development was suggested after exposure of mice to common endocrine disrupting chemicals (EDCs) present in the environmental. These authors found that after exposure to EDCs, the SOHLH2 protein and mRNA were downregulated and as a consequence, these mice presented an impaired primordial follicular development (Tran et al., 2018). |
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Entity | Epithelial Ovarian Cancer (EOC) |
Note | SOHLH2 seems to be related to EOC tumorigenesis. The SOHLH2 immunostaining was evaluated in tumors from 65 EOC patients, and it was observed that those with SOHLH2 negative tumors presented lower overall survival as compared to positive tumors. In vitro studies were conducted to assess the impact of SOHLH2 in the cellular growth of EOC derived cell lines and obtained data showed that SOHLH2 overexpression inhibited proliferation of HO8910 and OVCAR3 cells. In accordance with that, the injection of HO8910 overexpressing SOHLH2 in nude mice caused a lower tumor growth rate as compared to the control group. The mechanism involved in this reduced tumor growth seems to be associated with the induction of CDKN1A (also designated WAF1/CIP1 or "p21") and inhibition of CCND1 (cyclin D1) expression as observed in HO8910 overexpressing SOHLH2. These data suggest that SOHLH2 might act as a tumor suppressor in EOC (Zhang et al., 2014). In another study, the SOHLH2 reduction expression was significantly associated with distant metastasis as compared to borderline ovarian tumors and EOC without metastasis. Taking all these into consideration, SOHLH2 seems to play a role in EOC tumorigenesis and invasion (Zhang et al., 2016). |
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Entity | Breast Cancer |
Note | The overexpression of SOHLH2 in MDA-MB-231 cell line inhibited metastasis and epithelial-mesenchymal transition (EMT) by controlling transcription of CXCL8 (IL-8) through binding to its promoter region. On the other hands, SOHLH2 silence increased migration and invasion, suggesting that this protein may negatively regulate metastasis and play an important role in EMT (Ji et al., 2016). Primary breast tumors express reduced levels of SOHLH2 in comparison with normal tissue (Zhang et al., 2019). Also, SOHLH2 expression is associated to cellular proliferation in vitro and tumor growth in vivo acting as a tumor suppressor gene. The tumor suppressor effects on breast cancer seem to occur due to SOHLH2 inhibition of WNT/β-catenin through the increase of APC (Zhang et al., 2019) (figure 2). Previous data from our group have shown the association between SOHLH2 and triple negative breast cancer (TNBC). Patients with TNBC with reduced expression of SOHLH2 show shorter disease-free and a tendency to lower overall survival rates compared to patients with tumors with increased expression of SOHLH2, suggesting that SOHLH2 expression might be a potential candidate biomarker with potential prognostic value for TNBC. (De Alcantara Filho et al., 2018) |
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Sohlh2 is a germ cell-specific bHLH transcription factor |
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Gene Expr Patterns 2006 Oct;6(8):1014-8 |
PMID 16765102 |
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Basic helix-loop-helix transcription factors in evolution: Roles in development of mesoderm and neural tissues |
Gyoja F |
Genesis 2017 Sep;55(9) |
PMID 28804953 |
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Sohlh2 knockout mice are male-sterile because of degeneration of differentiating type A spermatogonia |
Hao J, Yamamoto M, Richardson TE, Chapman KM, Denard BS, Hammer RE, Zhao GQ, Hamra FK |
Stem Cells 2008 Jun;26(6):1587-97 |
PMID 18339773 |
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Sohlh2 suppresses epithelial to mesenchymal transition in breast cancer via downregulation of IL-8 |
Ji S, Zhang W, Zhang X, Hao C, Hao A, Gao Q, Zhang H, Sun J, Hao J |
Oncotarget 2016 Aug 2;7(31):49411-49424 |
PMID 27384482 |
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An overview of the basic helix-loop-helix proteins |
Jones S |
Genome Biol 2004;5(6):226 |
PMID 15186484 |
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Novel variants in the SOHLH2 gene are implicated in human premature ovarian failure |
Qin Y, Jiao X, Dalgleish R, Vujovic S, Li J, Simpson JL, Al-Azzawi F, Chen ZJ |
Fertil Steril 2014 Apr;101(4):1104-1109 |
PMID 24524832 |
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Genome-wide profiling of DNA methylation reveals a class of normally methylated CpG island promoters |
Shen L, Kondo Y, Guo Y, Zhang J, Zhang L, Ahmed S, Shu J, Chen X, Waterland RA, Issa JP |
PLoS Genet 2007 Oct;3(10):2023-36 |
PMID 17967063 |
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Transcription factors SOHLH1 and SOHLH2 coordinate oocyte differentiation without affecting meiosis I |
Shin YH, Ren Y, Suzuki H, Golnoski KJ, Ahn HW, Mico V, Rajkovic A |
J Clin Invest 2017 Jun 1;127(6):2106-2117 |
PMID 28504655 |
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Association of genetic variants in SOHLH1 and SOHLH2 with non-obstructive azoospermia risk in the Chinese population |
Song B, Zhang Y, He XJ, Du WD, Ruan J, Zhou FS, Wu H, Zha X, Xie XS, Ye L, Wei ZL, Zhou P, Cao YX |
Eur J Obstet Gynecol Reprod Biol 2015 Jan;184:48-52 |
PMID 25463635 |
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bHLH-Orange Transcription Factors in Development and Cancer |
Sun H, Ghaffari S, Taneja R |
Transl Oncogenomics 2007 Dec 10;2:107-20 |
PMID 23641148 |
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SOHLH1 and SOHLH2 coordinate spermatogonial differentiation |
Suzuki H, Ahn HW, Chu T, Bowden W, Gassei K, Orwig K, Rajkovic A |
Dev Biol 2012 Jan 15;361(2):301-12 |
PMID 22056784 |
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Auto-regulation of the Sohlh1 gene by the SOHLH2/SOHLH1/SP1 complex: implications for early spermatogenesis and oogenesis |
Toyoda S, Yoshimura T, Mizuta J, Miyazaki J |
PLoS One 2014 Jul 8;9(7):e101681 |
PMID 25003626 |
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Depletion of follicles accelerated by combined exposure to phthalates and 4-vinylcyclohexene diepoxide, leading to premature ovarian failure in rats |
Tran DN, Jung EM, Yoo YM, Ahn C, Kang HY, Choi KC, Hyun SH, Dang VH, Pham TN, Jeung EB |
Reprod Toxicol 2018 Sep;80:60-67 |
PMID 29969652 |
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Sohlh2 inhibits human ovarian cancer cell invasion and metastasis by transcriptional inactivation of MMP9 |
Zhang H, Hao C, Wang Y, Ji S, Zhang X, Zhang W, Zhao Q, Sun J, Hao J |
Mol Carcinog 2016 Jul;55(7):1127-37 |
PMID 26153894 |
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Sohlh2 inhibits ovarian cancer cell proliferation by upregulation of p21 and downregulation of cyclin D1 |
Zhang H, Zhang X, Ji S, Hao C, Mu Y, Sun J, Hao J |
Carcinogenesis 2014 Aug;35(8):1863-71 |
PMID 24858206 |
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Sohlh2 inhibits breast cancer cell proliferation by suppressing Wnt/β-catenin signaling pathway |
Zhang X, Liu R, Zhao N, Ji S, Hao C, Cui W, Zhang R, Hao J |
Mol Carcinog 2019 Feb 5 |
PMID 30720232 |
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