SETD2 (SET domain containing 2, histone lysine methyltransferase)

2020-07-01   Vivian Wang , Assunta De Rienzo 

Division of Thoracic Surgery, Brigham and Womens Hospital and Harvard Medical School, Boston, USA;;




Review of SETD2 and its role in cancer



SETD2 gene spans 147 kb. It is composed of 26 exons encoding three mRNA transcript variants ranging from 8,452 to 8,737 nucleotides in length.


Transcription start is 189 bp for variant 1 and 305 bp for variant 2 upstream of the first ATG of the SETD2 ORF. Variant 2 differs in the 5 UTR and coding sequence compared with variant 1, resulting in a shorter isoform of the SETD2 protein. A third non-coding variant contains an alternate exon compared with variant 1.


No SETD2 pseudogene has been reported.


Atlas Image
Graphic representation of SETD2 protein. SETD2 (isoform 1) is a 2564 aa protein. AWS, associated with SET; SET, Su(var)3-9, enhancer-of-zeste, trithorax; PS, post-SET; WW, rsp5-domain; CC, coiled-coil; LCR, low-charged region; SRI, Set2 Rpb1 Interacting.


Human SETD2 is a methyltransferase with 2 main isoforms. Isoform 1 is 2,564 amino acids with a molecular weight of 287.5 kDa. Isoform 2 is 44 residues shorter than isoform 1 at the N-terminus, and is 2520 amino acids with a molecular weight of 282.6 kDa. Three conserved functional domains have been identified in the SETD2: the triplicate AWS-SET-PostSET domains, a WW domain, and a Set2 Rpb1 Interacting (SRI) domain (Li et al., 2016).
The triplicate AWS-SET-PostSET domain mediates methyltransferase activity specific for histone H3 lysine 36 (H3K36) (Edmunds et al., 2008), and a few other non-histone targets (Park et al., 2016). The SET (Suppressor of Variegation, Enhancer of zeste and Trithorax) domain is an evolutionarily conserved motif of 130 amino acids (Rea et al., 2000; Tschiersch et al., 1994), usually present as part of a multi-domain where it is flanked by an AWS (Associated with SET domain) and a PostSET domain. It includes a beta-sheet structure that facilitates multiple rounds of methylation without substrate disassociation (Zhang et al., 2003).
The WW domain, located in the C-terminal region of SETD2, contains two conserved tryptophan (W) residues (Sudol et al., 1995). The WW domain preferentially binds proline-rich segments of other proteins, mediating protein-protein interactions, such as the proline-rich motifs in the Huntingtin protein in Huntingtons disease (Gao et al., 2014).
The SRI domain encompasses a 79 amino acid region towards the C-terminal end of SETD2 and is the primary docking site of RNA Pol II (Li et al., 2005; Kizer et al., 2005). It is composed of a low charged region rich in glutamine and proline. Human SETD2 associates with hyperphosphorylated C-terminal domain (CTD) of RNA polymerase II (RNAPII), linking SETD2 to the transcription elongation process (Li et al., 2002). In yeast, deletion of the CTD region on RNA polymerase II defects trimethylation of H3K36, suggesting that H3K36 trimethylation and transcription elongation are coupled processes (Krogan et al., 2003).


SETD2 is ubiquitously expressed in all human tissues and cell lines tested, including many cancer-derived cell lines. Expression is relatively high in bone marrow, lymph node, testis and thyroid tissue, and it is relatively low in pancreas, heart and salivary gland tissue (Fagerberg et al., 2014).


SETD2 localizes as nuclear speckles and additionally in cytosol.


SETD2 is a lysine methyltransferase and transcriptional regulator involved in histone modification, DNA repair, mRNA regulation, genomic stability, alternative splicing, and interferon-α signaling (Aymard et al., 2014; Skucha, et al., 2019; Luco et al., 2010; de Almeida et al., 2011). The C-terminal end of SETD2 complexes with Heterogeneous Nuclear Ribonucleoprotein L ( HNRNPL) and mediates a non-redundant, co-transcriptional trimethylation to histone H3 at lysine 36 (H3K36me). (Yuan et al., 2009) It was demonstrated that Setd2, the mouse homologue of human Huntingtin-interacting protein HYPB, can modulate all detectable K36me3, but not K36me2 or K36me1, throughout the nucleus using siRNA experiments (Edmunds et al., 2008). Similarly, in yeast, knockdown of Setd2 results in complete absence of H3Kme3 without affecting H3Kme1 or H3Kme2. Loss of SETD2 is associated with greater chromatin accessibility (Carvalho et al., 2014; Simon et al., 2014).
In addition to H3K36, SETD2 methylates two other non-histone targets: the α-tubulin on lysine 40 of mitotic microtubules (Park et al., 2016) and the signal transducer and transcription activator ( STAT1) on lysine 525 (Chen et al., 2017).
SETD2 is also a critical amplifier of interferon-α signaling as STAT1 methylation on lysine 525 catalyzed by SETD2 is an essential signaling event on the induction of interferon stimulating genes, such as ISG15 and MX2 (Chen et al., 2017).
The C-terminal domain of SETD2 has been shown to interact with the tumor suppressor TP53, and modulate the expression of its downstream target genes (Xie et al., 2008; Carvalho et al., 2019).


The AWS-SET-postSET domains in human SETD2 share sequence homology and functional similarity with those in yeast Setd2. The SET domain that mediates methyltransferase activity is a ~130 amino acid sequence motif that is evolutionarily conserved from mammals to yeast and even in some bacteria and viruses (Rea et al., 2000; Tschiersch et al., 1994).



Inactivating SETD2 mutations are common in clear cell renal cell cancer but have been identified also in other cancers including lung cancer, acute lymphoblastic leukemia, and glioma (Fahey and Davis, 2017). The majority of somatic SETD2 mutations are missense mutations (Li et al., 2016). SETD2-deficient cancers exhibit a wide range of mutations, including insertions, deletions, and chromosomal aberrations, suggesting an additional role for SETD2 in genome stability (Li et al., 2016). Homozygous deletion of Setd2 in mice has been shown to result in embryonic lethality (Hu et al., 2010).

Implicated in

Entity name
Clear cell renal cell carcinoma (ccRCC)
The overall frequency of SETD2 mutations in ccRCC is approximately 15.6% (Cancer Genome Atlas Research Network, 2013). SETD2 mutations were found to be associated with shorter cancer-specific survival (P = 0.036; HR 1.68; 95% CI 1.04-2.73) (Hakimi et al., 2013). The presence of SETD2 mutations was a predictor of ccRCC recurrence. The fraction of truncating SETD2 mutations in ccRCC (57%) was significantly higher than the fraction of truncating SETD2 mutations in non-ccRCC tumors (32%).
Entity name
Pancreatic adenocarcinoma
Low SETD2 expression was correlated with poor prognosis in patients with pancreatic adenocarcinoma. In vivo, Setd2 loss in murine pancreatic acinar cells facilitated Kras-induced acinar-to-ductal reprogramming, mainly through epigenetic dysregulation of Fbxw7. This suggests that Setd2 may act as a putative tumor suppressor in Kras-driven pancreatic carcinogenesis. A Setd2 ablation in murine pancreatic cancer cells enhanced epithelial-mesenchymal transition (EMT) through impaired epigenetic regulation of a-catenin (Ctnna1). Setd2 deficiency in murine pancreatic cancer cell lines also led to sustained Akt activation (Niu et al., 2020).
Entity name
Malignant Mesothelioma (MM):
SETD2 is located in a region frequently lost in malignant pleural mesothelioma (MPM). In 2016, a comprehensive genomic analysis of 212 MPM patients identified SETD2 to be frequently mutated in this disease. In addition, gene fusions and splice-site alterations were also frequent mechanisms for inactivation of SETD2 in MPM (Bueno et al., 2016). In a cohort of 33 malignant mesotheliomas, 27% showed minute biallelic deletions or loss of heterozygosity combined with point mutations in SETD2 by using combined high-density comparative genomic hybridization array and whole exome sequencing analyses (Yoshikawa et al., 2015).
Entity name
Acute Leukemia
SETD2 mutations have been found to be frequent (22%) in acute lymphoid and myeloid leukemias (ALL and AML) carrying a mixed lineage leukemia (MLL)-rearrangement. Knockdown of SETD2 in pre-leukemic cells carrying a KMT2A (MLL) fusion-gene increased both clonogenicity and proliferation of these cells, suggesting that loss of function of SETD2 may promote progression of the disease. In acute leukemia, SETD2 was found mutated in 6% of cases (Zhu et al., 2014). These mutations were commonly nonsense or frameshift, mostly affecting the SRI domain, and approximately a quarter of samples carried bi-allelic SETD2 mutations. A comparison of matched primary and relapsed ALL samples suggested that mutations in epigenetic regulators as a class, including SETD2 mutations, were more common at relapse (Mar et al., 2014).
Entity name
Gastrointestinal Stromal Tumors
SETD2 loss has been associated with more aggressive gastrointestinal stromal tumors (Huang et al., 2016).
Entity name
Lung Adenocarcinoma
SETD2 mutations were found to occur in 9% of lung adenocarcinomas (Cancer Genome Atlas Research Network, 2015). SETD2 fusion mutations are more common than point mutations in lung adenocarcinoma (Lee et al., 2019; Rosell et al., 2020). It has been also shown that suppression of SETD2 or CREB1 confers resistance to cisplatin through inhibition of H3K36me3 and ERK activation in non-small cell lung cancer cell lines (Kim et al., 2019).
Entity name
Lung Neuroendocrine Tumors
Genome wide SNP array analysis of 11 well-differentiated pulmonary carcinoid tumors has revealed loss of heterozygosity of SETD2 in these tumors (Cros et al., 2020).
Entity name
Primary Central Nervous System Tumors
A study published in 2013 showed that 15-28% of pediatric high-grade gliomas (HGGs) and 8% of adult HGGs displayed SETD2 mutations (Fontebasso et al., 2013).
Entity name
Bladder Carcinoma
SETD2 mutations have been observed in 6-10% of bladder urothelial carcinomas (Van Allen et al., 2014).
Entity name
Huntingtons Disease
SETD2 was first identified as a huntingtin-interacting protein, implicated in the pathogenesis of Huntingtons disease (Faber et al., 1998). The WW domain of SETD2 was found to interact with the N-terminal PRR region of huntingtin protein. (Passani et al., 2000). A stretch of polyproline residues preceding the WW domain was found to modulate the interaction between the SETD2 and huntingtin proteins (Gao et al., 2014).


Pubmed IDLast YearTitleAuthors
250795522014Comprehensive molecular profiling of lung adenocarcinoma.
246583502014Transcriptionally active chromatin recruits homologous recombination at DNA double-strand breaks.Aymard F et al
269282272016Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations.Bueno R et al
248430022014SETD2 is required for DNA double-strand break repair and activation of the p53-mediated checkpoint.Carvalho S et al
287534262017Methyltransferase SETD2-Mediated Methylation of STAT1 Is Critical for Interferon Antiviral Activity.Chen K et al
320152332021Specific Genomic Alterations in High-Grade Pulmonary Neuroendocrine Tumours with Carcinoid Morphology.Cros J et al
181570862008Dynamic histone H3 methylation during gene induction: HYPB/Setd2 mediates all H3K36 trimethylation.Edmunds JW et al
97002021998Huntingtin interacts with a family of WW domain proteins.Faber PW et al
281598332017SETting the Stage for Cancer Development: SETD2 and the Consequences of Lost Methylation.Fahey CC et al
234177122013Mutations in SETD2 and genes affecting histone H3K36 methylation target hemispheric high-grade gliomas.Fontebasso AM et al
244123942014Autoinhibitory structure of the WW domain of HYPB/SETD2 regulates its interaction with the proline-rich region of huntingtin.Gao YG et al
236204062013Adverse outcomes in clear cell renal cell carcinoma with mutations of 3p21 epigenetic regulators BAP1 and SETD2: a report by MSKCC and the KIRC TCGA research network.Hakimi AA et al
201336252010Histone H3 lysine 36 methyltransferase Hypb/Setd2 is required for embryonic vascular remodeling.Hu M et al
263388262016SETD2 histone modifier loss in aggressive GI stromal tumours.Huang KK et al
300936302019Acquired SETD2 mutation and impaired CREB1 activation confer cisplatin resistance in metastatic non-small cell lung cancer.Kim IK et al
157982142005A novel domain in Set2 mediates RNA polymerase II interaction and couples histone H3 K36 methylation with transcript elongation.Kizer KO et al
127735642003Methylation of histone H3 by Set2 in Saccharomyces cerevisiae is linked to transcriptional elongation by RNA polymerase II.Krogan NJ et al
311552352019Tracing Oncogene Rearrangements in the Mutational History of Lung Adenocarcinoma.Lee JJ et al
236222432013The histone mark H3K36me3 regulates human DNA mismatch repair through its interaction with MutSα.Li F et al
271918912016SETD2: an epigenetic modifier with tumor suppressor functionality.Li J et al
123817232002Association of the histone methyltransferase Set2 with RNA polymerase II plays a role in transcription elongation.Li J et al
201335232010Regulation of alternative splicing by histone modifications.Luco RF et al
246622452014Mutations in epigenetic regulators including SETD2 are gained during relapse in paediatric acute lymphoblastic leukaemia.Mar BG et al
313005132020Loss of Setd2 promotes Kras-induced acinar-to-ductal metaplasia and epithelia-mesenchymal transition during pancreatic carcinogenesis.Niu N et al
275185652016Dual Chromatin and Cytoskeletal Remodeling by SETD2.Park IY et al
109586562000Huntingtin's WW domain partners in Huntington's disease post-mortem brain fulfill genetic criteria for direct involvement in Huntington's disease pathogenesis.Passani LA et al
109492932000Regulation of chromatin structure by site-specific histone H3 methyltransferases.Rea S et al
315997702020Novel molecular targets for the treatment of lung cancer.Rosell R et al
241586552014Variation in chromatin accessibility in human kidney cancer links H3K36 methyltransferase loss with widespread RNA processing defects.Simon JM et al
308187622019Roles of SETD2 in Leukemia-Transcription, DNA-Damage, and Beyond.Skucha A et al
76418871995Characterization of a novel protein-binding module--the WW domain.Sudol M et al
79152321994The protein encoded by the Drosophila position-effect variegation suppressor gene Su(var)3-9 combines domains of antagonistic regulators of homeotic gene complexes.Tschiersch B et al
250962332014Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma.Van Allen EM et al
185850042008Histone methyltransferase protein SETD2 interacts with p53 and selectively regulates its downstream genes.Xie P et al
249166742015Biallelic germline and somatic mutations in malignant mesothelioma: multiple mutations in transcription regulators including mSWI/SNF genes.Yoshikawa Y et al
128879032003Structural basis for the product specificity of histone lysine methyltransferases.Zhang X et al
245094772014Identification of functional cooperative mutations of SETD2 in human acute leukemia.Zhu X et al
217921932011Splicing enhances recruitment of methyltransferase HYPB/Setd2 and methylation of histone H3 Almeida SF et al

Other Information

Locus ID:

NCBI: 29072
MIM: 612778
HGNC: 18420
Ensembl: ENSG00000181555


dbSNP: 29072
ClinVar: 29072
TCGA: ENSG00000181555


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Lysine degradationKEGGko00310
Lysine degradationKEGGhsa00310
Chromatin organizationREACTOMER-HSA-4839726
Chromatin modifying enzymesREACTOMER-HSA-3247509
PKMTs methylate histone lysinesREACTOMER-HSA-3214841

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
200542972010Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes.458
249316102014SETD2-dependent histone H3K36 trimethylation is required for homologous recombination repair and genome stability.134
236204062013Adverse outcomes in clear cell renal cell carcinoma with mutations of 3p21 epigenetic regulators BAP1 and SETD2: a report by MSKCC and the KIRC TCGA research network.124
191414752008The Iws1:Spt6:CTD complex controls cotranscriptional mRNA biosynthesis and HYPB/Setd2-mediated histone H3K36 methylation.106
205018572010Histone methyltransferase gene SETD2 is a novel tumor suppressor gene in clear cell renal cell carcinoma.96
234177122013Mutations in SETD2 and genes affecting histone H3K36 methylation target hemispheric high-grade gliomas.94
161182272005Identification and characterization of a novel human histone H3 lysine 36-specific methyltransferase.91
161182272005Identification and characterization of a novel human histone H3 lysine 36-specific methyltransferase.91
245094772014Identification of functional cooperative mutations of SETD2 in human acute leukemia.88
191552142009Histone H3 lysine 36 dimethylation (H3K36me2) is sufficient to recruit the Rpd3s histone deacetylase complex and to repress spurious transcription.84


Vivian Wang ; Assunta De Rienzo

SETD2 (SET domain containing 2, histone lysine methyltransferase)

Atlas Genet Cytogenet Oncol Haematol. 2020-07-01

Online version: