[Frontiers in Bioscience, Landmark, 25, 781-797, Jan 1, 2020]

SETD2, an epigenetic tumor suppressor: a focused review on GI tumor

Ming Hu1, Mu Hu2, Qin Zhang3, Jin-ping Lai4, Xiu-li Liu1

1Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA, 2Department of Orthopaedics, Ruijin Hospital North, School of Medicine, Shanghai Jiaotong University, Shanghai, China, 3Department of Pathology, Third Central Hospital of Nankai University, Tianjin, China, 4Department of Pathology and Laboratory Medicine, Kaiser Permanente Sacramento Medical Center, Sacramento, CA, USA


1. Abstract
2. Introduction
3. The tumor suppressor function of SETD2 in gastrointestinal cancer
    3.1. Regulation of SETD2 expression level in GI tumors
    3.2. SETD2 mutations in GI tumors
4. Potential mechanism of SETD2 regulating GI tumor progression
    4.1. SETD2 and gene transcription
    4.2. SETD2 and mRNA splicing
    4.3. SETD2 and DNA replication stress
    4.4. SETD2 and DNA damage repair
    4.5. SETD2 regulation of mitosis by tubulin methylation
    4.6. SETD2 and immune deregulation
    4.7. SETD2 and chemoresistance
5. Conclusion and perspectives
6. Acknowledgments
7. References


Significant progress has been made in our understanding of the role of epigenetic modifiers in many types of human cancer. Here, we review currently available studies on the unique histone methyltransferase, SETD2, which is responsible for H3 lysine 36 tri-methylation (H3K36me3). SETD2 plays pivotal roles in RNA alternative splicing regulation, DNA damage repair, and cytoskeleton protein methylation; inactivation of SETD2 and resultant dysregulation of these functions may lead to tumorigenesis. Despite being a newly discovered tumor suppressor, SETD2 has been found to be mutated in multiple types of cancer, including gastrointestinal tumor. Some tumors can acquire a selective growth advantage after SETD2 inactivation, which could happen in different stages in tumor progression. Decreased level of H3K36me3 caused by SETD2 inactivation has been shown to associate with higher tumor grade, tumor stage, metastasis risk, and shorter survival. Some studies also suggest that SETD2 mutation is associated with therapy resistance, therefore these SETD2-deficient tumors may need different therapeutic strategies.


1. M. K. Ng and P. Cheung: A brief histone in time: understanding the combinatorial functions of histone PTMs in the nucleosome context. In: Biochem Cell Biol. (2016)
DOI: 10.1139/bcb-2015-0031

2. J. C. Black, C. Van Rechem and J. R. Whetstine: Histone lysine methylation dynamics: establishment, regulation, and biological impact. Mol Cell, 48(4), 491-507 (2012)
DOI: 10.1016/j.molcel.2012.11.006

3. A. Barski, S. Cuddapah, K. Cui, T. Y. Roh, D. E. Schones, Z. Wang, G. Wei, I. Chepelev and K. Zhao: High-resolution profiling of histone methylations in the human genome. Cell, 129(4), 823-37 (2007)
DOI: 10.1016/j.cell.2007.05.009

4. T. S. Mikkelsen, M. Ku, D. B. Jaffe, B. Issac, E. Lieberman, G. Giannoukos, P. Alvarez, W. Brockman, T. K. Kim, R. P. Koche, W. Lee, E. Mendenhall, A. O'Donovan, A. Presser, C. Russ, X. Xie, A. Meissner, M. Wernig, R. Jaenisch, C. Nusbaum, E. S. Lander and B. E. Bernstein: Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature, 448(7153), 553-60 (2007)
DOI: 10.1038/nature06008

5. B. D. Strahl, P. A. Grant, S. D. Briggs, Z. W. Sun, J. R. Bone, J. A. Caldwell, S. Mollah, R. G. Cook, J. Shabanowitz, D. F. Hunt and C. D. Allis: Set2 is a nucleosomal histone H3-selective methyltransferase that mediates transcriptional repression. Mol Cell Biol, 22(5), 1298-306 (2002)
DOI: 10.1128/mcb.

6. X. J. Sun, J. Wei, X. Y. Wu, M. Hu, L. Wang, H. H. Wang, Q. H. Zhang, S. J. Chen, Q. H. Huang and Z. Chen: Identification and characterization of a novel human histone H3 lysine 36-specific methyltransferase. J Biol Chem, 280(42), 35261-71 (2005)
DOI: 10.1074/jbc.M504012200

7. X. J. Sun, P. F. Xu, T. Zhou, M. Hu, C. T. Fu, Y. Zhang, Y. Jin, Y. Chen, S. J. Chen, Q. H. Huang, T. X. Liu and Z. Chen: Genome-wide survey and developmental expression mapping of zebrafish SET domain-containing genes. PLoS One, 3(1), e1499 (2008)
DOI: 10.1371/journal.pone.0001499

8. J. W. Edmunds, L. C. Mahadevan and A. L. Clayton: Dynamic histone H3 methylation during gene induction: HYPB/Setd2 mediates all H3K36 trimethylation. Embo j, 27(2), 406-20 (2008)
DOI: 10.1038/sj.emboj.7601967

9. M. Hu, X. J. Sun, Y. L. Zhang, Y. Kuang, C. Q. Hu, W. L. Wu, S. H. Shen, T. T. Du, H. Li, F. He, H. S. Xiao, Z. G. Wang, T. X. Liu, H. Lu, Q. H. Huang, S. J. Chen and Z. Chen: Histone H3 lysine 36 methyltransferase Hypb/Setd2 is required for embryonic vascular remodeling. Proc Natl Acad Sci U S A, 107(7), 2956-61 (2010)
DOI: 10.1073/pnas.0915033107

10. H. N. Du, I. M. Fingerman and S. D. Briggs: Histone H3 K36 methylation is mediated by a trans-histone methylation pathway involving an interaction between Set2 and histone H4. Genes Dev, 22(20), 2786-98 (2008)
DOI: 10.1101/gad.1700008

11. Y. Wang, Y. Niu and B. Li: Balancing acts of SRI and an auto-inhibitory domain specify Set2 function at transcribed chromatin. Nucleic Acids Res, 43(10), 4881-92 (2015)
DOI: 10.1093/nar/gkv393

12. Y. L. Zhang, J. W. Sun, Y. Y. Xie, Y. Zhou, P. Liu, J. C. Song, C. H. Xu, L. Wang, D. Liu, A. N. Xu, Z. Chen, S. J. Chen, X. J. Sun and Q. H. Huang: Setd2 deficiency impairs hematopoietic stem cell self-renewal and causes malignant transformation. Cell Res, 28(4), 476-490 (2018)
DOI: 10.1038/s41422-018-0015-9

13. H. Yuan, N. Li, D. Fu, J. Ren, J. Hui, J. Peng, Y. Liu, T. Qiu, M. Jiang, Q. Pan, Y. Han, X. Wang, Q. Li and J. Qin: Histone methyltransferase SETD2 modulates alternative splicing to inhibit intestinal tumorigenesis. J Clin Invest, 127(9), 3375-3391 (2017)
DOI: 10.1172/jci94292

14. Y. Zhou, X. Yan, X. Feng, J. Bu, Y. Dong, P. Lin, Y. Hayashi, R. Huang, A. Olsson, P. R. Andreassen, H. L. Grimes, Q. F. Wang, T. Cheng, Z. Xiao, J. Jin and G. Huang: Setd2 regulates quiescence and differentiation of adult hematopoietic stem cells by restricting RNA polymerase II elongation. Haematologica, 103(7), 1110-1123 (2018)
DOI: 10.3324/haematol.2018.187708

15. Y. Zhang, S. Xie, Y. Zhou, Y. Xie, P. Liu, M. Sun, H. Xiao, Y. Jin, X. Sun, Z. Chen, Q. Huang and S. Chen: H3K36 histone methyltransferase Setd2 is required for murine embryonic stem cell differentiation toward endoderm. Cell Rep, 8(6), 1989-2002 (2014)
DOI: 10.1016/j.celrep.2014.08.031

16. X. Yi, Y. Tao, X. Lin, Y. Dai, T. Yang, X. Yue, X. Jiang, X. Li, D. S. Jiang, K. C. Andrade and J. Chang: Histone methyltransferase Setd2 is critical for the proliferation and differentiation of myoblasts. Biochim Biophys Acta Mol Cell Res, 1864(4), 697-707 (2017)
DOI: 10.1016/j.bbamcr.2017.01.012

17. G. L. Dalgliesh, K. Furge, C. Greenman, L. Chen, G. Bignell, A. Butler, H. Davies, S. Edkins, C. Hardy, C. Latimer, J. Teague, J. Andrews, S. Barthorpe, D. Beare, G. Buck, P. J. Campbell, S. Forbes, M. Jia, D. Jones, H. Knott, C. Y. Kok, K. W. Lau, C. Leroy, M. L. Lin, D. J. McBride, M. Maddison, S. Maguire, K. McLay, A. Menzies, T. Mironenko, L. Mulderrig, L. Mudie, S. O'Meara, E. Pleasance, A. Rajasingham, R. Shepherd, R. Smith, L. Stebbings, P. Stephens, G. Tang, P. S. Tarpey, K. Turrell, K. J. Dykema, S. K. Khoo, D. Petillo, B. Wondergem, J. Anema, R. J. Kahnoski, B. T. Teh, M. R. Stratton and P. A. Futreal: Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature, 463(7279), 360-3 (2010)
DOI: 10.1038/nature08672

18. B. G. Mar, L. B. Bullinger, K. M. McLean, P. V. Grauman, M. H. Harris, K. Stevenson, D. S. Neuberg, A. U. Sinha, S. E. Sallan, L. B. Silverman, A. L. Kung, L. Lo Nigro, B. L. Ebert and S. A. Armstrong: Mutations in epigenetic regulators including SETD2 are gained during relapse in paediatric acute lymphoblastic leukaemia. Nat Commun, 5, 3469 (2014)
DOI: 10.1038/ncomms4469

19. A. M. Fontebasso, J. Schwartzentruber, D. A. Khuong-Quang, X. Y. Liu, D. Sturm, A. Korshunov, D. T. Jones, H. Witt, M. Kool, S. Albrecht, A. Fleming, D. Hadjadj, S. Busche, P. Lepage, A. Montpetit, A. Staffa, N. Gerges, M. Zakrzewska, K. Zakrzewski, P. P. Liberski, P. Hauser, M. Garami, A. Klekner, L. Bognar, G. Zadeh, D. Faury, S. M. Pfister, N. Jabado and J. Majewski: Mutations in SETD2 and genes affecting histone H3K36 methylation target hemispheric high-grade gliomas. Acta Neuropathol, 125(5), 659-69 (2013)
DOI: 10.1007/s00401-013-1095-8

20. X. Zhu, F. He, H. Zeng, S. Ling, A. Chen, Y. Wang, X. Yan, W. Wei, Y. Pang, H. Cheng, C. Hua, Y. Zhang, X. Yang, X. Lu, L. Cao, L. Hao, L. Dong, W. Zou, J. Wu, X. Li, S. Zheng, J. Yan, J. Zhou, L. Zhang, S. Mi, X. Wang, L. Zhang, Y. Zou, Y. Chen, Z. Geng, J. Wang, J. Zhou, X. Liu, J. Wang, W. Yuan, G. Huang, T. Cheng and Q. F. Wang: Identification of functional cooperative mutations of SETD2 in human acute leukemia. Nat Genet, 46(3), 287-93 (2014)
DOI: 10.1038/ng.2894

21. F. Bray, J. Ferlay, I. Soerjomataram, R. L. Siegel, L. A. Torre and A. Jemal: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 68(6), 394-424 (2018)
DOI: 10.3322/caac.21492

22. J. S. You and P. A. Jones: Cancer genetics and epigenetics: two sides of the same coin? Cancer Cell, 22(1), 9-20 (2012)
DOI: 10.1016/j.ccr.2012.06.008

23. G. Duns, E. van den Berg, I. van Duivenbode, J. Osinga, H. Hollema, R. M. Hofstra and K. Kok: Histone methyltransferase gene SETD2 is a novel tumor suppressor gene in clear cell renal cell carcinoma. Cancer Res, 70(11), 4287-91 (2010)
DOI: 10.1158/0008-5472.Can-10-0120

24. W. Al Sarakbi, W. Sasi, W. G. Jiang, T. Roberts, R. F. Newbold and K. Mokbel: The mRNA expression of SETD2 in human breast cancer: correlation with clinico-pathological parameters. BMC Cancer, 9, 290 (2009)
DOI: 10.1186/1471-2407-9-290

25. J. Li, G. Duns, H. Westers, R. Sijmons, A. van den Berg and K. Kok: SETD2: an epigenetic modifier with tumor suppressor functionality. Oncotarget, 7(31), 50719-50734 (2016)
DOI: 10.18632/oncotarget.9368

26. G. Duns, R. M. Hofstra, J. G. Sietzema, H. Hollema, I. van Duivenbode, A. Kuik, C. Giezen, O. Jan, J. J. Bergsma, H. Bijnen, P. van der Vlies, E. van den Berg and K. Kok: Targeted exome sequencing in clear cell renal cell carcinoma tumors suggests aberrant chromatin regulation as a crucial step in ccRCC development. Hum Mutat, 33(7), 1059-62 (2012)
DOI: 10.1002/humu.22090

27. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature, 499(7456), 43-9 (2013)
DOI: 10.1038/nature12222

28. Y. Sato, T. Yoshizato, Y. Shiraishi, S. Maekawa, Y. Okuno, T. Kamura, T. Shimamura, A. Sato-Otsubo, G. Nagae, H. Suzuki, Y. Nagata, K. Yoshida, A. Kon, Y. Suzuki, K. Chiba, H. Tanaka, A. Niida, A. Fujimoto, T. Tsunoda, T. Morikawa, D. Maeda, H. Kume, S. Sugano, M. Fukayama, H. Aburatani, M. Sanada, S. Miyano, Y. Homma and S. Ogawa: Integrated molecular analysis of clear-cell renal cell carcinoma. Nat Genet, 45(8), 860-7 (2013)
DOI: 10.1038/ng.2699

29. Z. Chen, C. Raghoonundun, W. Chen, Y. Zhang, W. Tang, X. Fan and X. Shi: SETD2 indicates favourable prognosis in gastric cancer and suppresses cancer cell proliferation, migration, and invasion. Biochem Biophys Res Commun, 498(3), 579-585 (2018)
DOI: 10.1016/j.bbrc.2018.03.022

30. L. Tang, W. Zhang, B. Su and B. Yu: Long noncoding RNA HOTAIR is associated with motility, invasion, and metastatic potential of metastatic melanoma. Biomed Res Int, 2013, 251098 (2013)
DOI: 10.1155/2013/251098

31. H. Li, J. An, M. Wu, Q. Zheng, X. Gui, T. Li, H. Pu and D. Lu: LncRNA HOTAIR promotes human liver cancer stem cell malignant growth through downregulation of SETD2. Oncotarget, 6(29), 27847-64 (2015)
DOI: 10.18632/oncotarget.4443

32. K. Zhu, P. J. Lei, L. G. Ju, X. Wang, K. Huang, B. Yang, C. Shao, Y. Zhu, G. Wei, X. D. Fu, L. Li and M. Wu: SPOP-containing complex regulates SETD2 stability and H3K36me3-coupled alternative splicing. Nucleic Acids Res, 45(1), 92-105 (2017)
DOI: 10.1093/nar/gkw814

33. K. K. Huang, J. R. McPherson, S. T. Tay, K. Das, I. B. Tan, C. C. Ng, N. Y. Chia, S. L. Zhang, S. S. Myint, L. Hu, V. Rajasegaran, D. Huang, J. L. Loh, A. Gan, A. N. Sairi, X. X. Sam, L. T. Dominguez, M. Lee, K. C. Soo, L. L. Ooi, H. S. Ong, A. Chung, P. K. Chow, W. K. Wong, S. Selvarajan, C. K. Ong, K. H. Lim, T. Nandi, S. Rozen, B. T. Teh, R. Quek and P. Tan: SETD2 histone modifier loss in aggressive GI stromal tumours. Gut, 65(12), 1960-1972 (2016)
DOI: 10.1136/gutjnl-2015-309482

34. T. Ryba, I. Hiratani, J. Lu, M. Itoh, M. Kulik, J. Zhang, T. C. Schulz, A. J. Robins, S. Dalton and D. M. Gilbert: Evolutionarily conserved replication timing profiles predict long-range chromatin interactions and distinguish closely related cell types. Genome Res, 20(6), 761-70 (2010)
DOI: 10.1101/gr.099655.109

35. S. Roy, W. A. LaFramboise, T. C. Liu, D. Cao, A. Luvison, C. Miller, M. A. Lyons, R. J. O'Sullivan, A. H. Zureikat, M. E. Hogg, A. Tsung, K. K. Lee, N. Bahary, R. E. Brand, J. S. Chennat, K. E. Fasanella, K. McGrath, M. N. Nikiforova, G. I. Papachristou, A. Slivka, H. J. Zeh and A. D. Singhi: Loss of Chromatin-Remodeling Proteins and/or CDKN2A Associates With Metastasis of Pancreatic Neuroendocrine Tumors and Reduced Patient Survival Times. Gastroenterology, 154(8), 2060-2063.e8 (2018)
DOI: 10.1053/j.gastro.2018.02.026

36. A. Puccini, H. J. Lenz, J. L. Marshall, D. Arguello, D. Raghavan, W. M. Korn, B. A. Weinberg, K. Poorman, A. L. Heeke, P. A. Philip, A. F. Shields, R. M. Goldberg and M. E. Salem: Impact of Patient Age on Molecular Alterations of Left-Sided Colorectal Tumors. Oncologist, 24(3), 319-326 (2019)
DOI: 10.1634/theoncologist.2018-0117

37. M. Gerlinger, A. J. Rowan, S. Horswell, M. Math, J. Larkin, D. Endesfelder, E. Gronroos, P. Martinez, N. Matthews, A. Stewart, P. Tarpey, I. Varela, B. Phillimore, S. Begum, N. Q. McDonald, A. Butler, D. Jones, K. Raine, C. Latimer, C. R. Santos, M. Nohadani, A. C. Eklund, B. Spencer-Dene, G. Clark, L. Pickering, G. Stamp, M. Gore, Z. Szallasi, J. Downward, P. A. Futreal and C. Swanton: Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med, 366(10), 883-892 (2012)
DOI: 10.1056/NEJMoa1113205

38. T. H. Ho, I. Y. Park, H. Zhao, P. Tong, M. D. Champion, H. Yan, F. A. Monzon, A. Hoang, P. Tamboli, A. S. Parker, R. W. Joseph, W. Qiao, K. Dykema, N. M. Tannir, E. P. Castle, R. Nunez-Nateras, B. T. Teh, J. Wang, C. L. Walker, M. C. Hung and E. Jonasch: High-resolution profiling of histone h3 lysine 36 trimethylation in metastatic renal cell carcinoma. Oncogene, 35(12), 1565-74 (2016)
DOI: 10.1038/onc.2015.221

39. A. A. Hakimi, Y. B. Chen, J. Wren, M. Gonen, O. Abdel-Wahab, A. Heguy, H. Liu, S. Takeda, S. K. Tickoo, V. E. Reuter, M. H. Voss, R. J. Motzer, J. A. Coleman, E. H. Cheng, P. Russo and J. J. Hsieh: Clinical and pathologic impact of select chromatin-modulating tumor suppressors in clear cell renal cell carcinoma. Eur Urol, 63(5), 848-54 (2013)
DOI: 10.1016/j.eururo.2012.09.005

40. A. A. Hakimi, I. Ostrovnaya, B. Reva, N. Schultz, Y. B. Chen, M. Gonen, H. Liu, S. Takeda, M. H. Voss, S. K. Tickoo, V. E. Reuter, P. Russo, E. H. Cheng, C. Sander, R. J. Motzer and J. J. Hsieh: Adverse 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. Clin Cancer Res, 19(12), 3259-67 (2013)
DOI: 10.1158/1078-0432.Ccr-12-3886

41. M. K. Zeman and K. A. Cimprich: Causes and consequences of replication stress. Nat Cell Biol, 16(1), 2-9 (2014)
DOI: 10.1038/ncb2897

42. N. K. Altorki, G. J. Markowitz, D. Gao, J. L. Port, A. Saxena, B. Stiles, T. McGraw and V. Mittal: The lung microenvironment: an important regulator of tumour growth and metastasis. Nat Rev Cancer, 19(1), 9-31 (2019)
DOI: 10.1038/s41568-018-0081-9

43. P. Friedl and S. Alexander: Cancer invasion and the microenvironment: plasticity and reciprocity. Cell, 147(5), 992-1009 (2011)
DOI: 10.1016/j.cell.2011.11.016

44. S. K. Biswas: Metabolic Reprogramming of Immune Cells in Cancer Progression. Immunity, 43(3), 435-49 (2015)
DOI: 10.1016/j.immuni.2015.09.001

45. M. G. Vander Heiden and R. J. DeBerardinis: Understanding the Intersections between Metabolism and Cancer Biology. Cell, 168(4), 657-669 (2017)
DOI: 10.1016/j.cell.2016.12.039

46. M. V. Blagosklonny: Antiangiogenic therapy and tumor progression. Cancer Cell, 5(1), 13-17 (2004)
DOI: 10.1016/S1535-6108(03)00336-2

47. M. A. Nieto, R. Y. Huang, R. A. Jackson and J. P. Thiery: EMT: 2016. Cell, 166(1), 21-45 (2016)
DOI: 10.1016/j.cell.2016.06.028

48. K. O. Kizer, H. P. Phatnani, Y. Shibata, H. Hall, A. L. Greenleaf and B. D. Strahl: A novel domain in Set2 mediates RNA polymerase II interaction and couples histone H3 K36 methylation with transcript elongation. Mol Cell Biol, 25(8), 3305-16 (2005)
DOI: 10.1128/mcb.

49. S. X. Pfister, E. Markkanen, Y. Jiang, S. Sarkar, M. Woodcock, G. Orlando, I. Mavrommati, C. C. Pai, L. P. Zalmas, N. Drobnitzky, G. L. Dianov, C. Verrill, V. M. Macaulay, S. Ying, N. B. La Thangue, V. D'Angiolella, A. J. Ryan and T. C. Humphrey: Inhibiting WEE1 Selectively Kills Histone H3K36me3-Deficient Cancers by dNTP Starvation. Cancer Cell, 28(5), 557-568 (2015)
DOI: 10.1016/j.ccell.2015.09.015

50. J. X. Zhao, X. W. Li, B. Y. Shi, F. Wang, Z. R. Xu, H. L. Meng, Y. Y. Su, J. M. Wang, N. Xiao, Q. He, Y. P. Wang and Y. M. Fan: Effect of histone modifications on hMLH1 alternative splicing in gastric cancer. Tumour Biol, 39(4), 1010428317697546 (2017)
DOI: 10.1177/1010428317697546

51. J. Flach, S. T. Bakker, M. Mohrin, P. C. Conroy, E. M. Pietras, D. Reynaud, S. Alvarez, M. E. Diolaiti, F. Ugarte, E. C. Forsberg, M. M. Le Beau, B. A. Stohr, J. Mendez, C. G. Morrison and E. Passegue: Replication stress is a potent driver of functional decline in ageing haematopoietic stem cells. Nature, 512(7513), 198-202 (2014)
DOI: 10.1038/nature13619

52. N. Kanu, E. Gronroos, P. Martinez, R. A. Burrell, X. Yi Goh, J. Bartkova, A. Maya-Mendoza, M. Mistrik, A. J. Rowan, H. Patel, A. Rabinowitz, P. East, G. Wilson, C. R. Santos, N. McGranahan, S. Gulati, M. Gerlinger, N. J. Birkbak, T. Joshi, L. B. Alexandrov, M. R. Stratton, T. Powles, N. Matthews, P. A. Bates, A. Stewart, Z. Szallasi, J. Larkin, J. Bartek and C. Swanton: SETD2 loss-of-function promotes renal cancer branched evolution through replication stress and impaired DNA repair. Oncogene, 34(46), 5699-708 (2015)
DOI: 10.1038/onc.2015.24

53. I. Stec, S. B. Nagl, G. J. van Ommen and J. T. den Dunnen: The PWWP domain: a potential protein-protein interaction domain in nuclear proteins influencing differentiation? FEBS Lett, 473(1), 1-5 (2000)

54. T. Baubec, D. F. Colombo, C. Wirbelauer, J. Schmidt, L. Burger, A. R. Krebs, A. Akalin and D. Schubeler: Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation. Nature, 520(7546), 243-7 (2015)
DOI: 10.1038/nature14176

55. M. M. Pradeepa, H. G. Sutherland, J. Ule, G. R. Grimes and W. A. Bickmore: Psip1/Ledgf p52 binds methylated histone H3K36 and splicing factors and contributes to the regulation of alternative splicing. PLoS Genet, 8(5), e1002717 (2012)
DOI: 10.1371/journal.pgen.1002717

56. F. Li, G. Mao, D. Tong, J. Huang, L. Gu, W. Yang and G. M. Li: The histone mark H3K36me3 regulates human DNA mismatch repair through its interaction with MutSalpha. Cell, 153(3), 590-600 (2013)
DOI: 10.1016/j.cell.2013.03.025

57. S. X. Pfister, S. Ahrabi, L. P. Zalmas, S. Sarkar, F. Aymard, C. Z. Bachrati, T. Helleday, G. Legube, N. B. La Thangue, A. C. Porter and T. C. Humphrey: SETD2-dependent histone H3K36 trimethylation is required for homologous recombination repair and genome stability. Cell Rep, 7(6), 2006-18 (2014)
DOI: 10.1016/j.celrep.2014.05.026

58. I. Y. Park, R. T. Powell, D. N. Tripathi, R. Dere, T. H. Ho, T. L. Blasius, Y. C. Chiang, I. J. Davis, C. C. Fahey, K. E. Hacker, K. J. Verhey, M. T. Bedford, E. Jonasch, W. K. Rathmell and C. L. Walker: Dual Chromatin and Cytoskeletal Remodeling by SETD2. Cell, 166(4), 950-962 (2016)
DOI: 10.1016/j.cell.2016.07.005

59. K. Chen, J. Liu, S. Liu, M. Xia, X. Zhang, D. Han, Y. Jiang, C. Wang and X. Cao: Methyltransferase SETD2-Mediated Methylation of STAT1 Is Critical for Interferon Antiviral Activity. Cell, 170(3), 492-506.e14 (2017)
DOI: 10.1016/j.cell.2017.06.042

60. M. McKinney, A. B. Moffitt, P. Gaulard, M. Travert, L. De Leval, A. Nicolae, M. Raffeld, E. S. Jaffe, S. Pittaluga, L. Xi, T. Heavican, J. Iqbal, K. Belhadj, M. H. Delfau-Larue, V. Fataccioli, M. B. Czader, I. S. Lossos, J. R. Chapman-Fredricks, K. L. Richards, Y. Fedoriw, S. L. Ondrejka, E. D. Hsi, L. Low, D. Weisenburger, W. C. Chan, N. Mehta-Shah, S. Horwitz, L. Bernal-Mizrachi, C. R. Flowers, A. W. Beaven, M. Parihar, L. Baseggio, M. Parrens, A. Moreau, P. Sujobert, M. Pilichowska, A. M. Evens, A. Chadburn, R. K. Au-Yeung, G. Srivastava, W. W. Choi, J. R. Goodlad, I. Aurer, S. Basic-Kinda, R. D. Gascoyne, N. S. Davis, G. Li, J. Zhang, D. Rajagopalan, A. Reddy, C. Love, S. Levy, Y. Zhuang, J. Datta, D. B. Dunson and S. S. Dave: The Genetic Basis of Hepatosplenic T-cell Lymphoma. Cancer Discov, 7(4), 369-379 (2017)
DOI: 10.1158/2159-8290.Cd-16-0330

61. B. G. Mar, S. H. Chu, J. D. Kahn, A. V. Krivtsov, R. Koche, C. A. Castellano, J. L. Kotlier, R. L. Zon, M. E. McConkey, J. Chabon, R. Chappell, P. V. Grauman, J. J. Hsieh, S. A. Armstrong and B. L. Ebert: SETD2 alterations impair DNA damage recognition and lead to resistance to chemotherapy in leukemia. Blood, 130(24), 2631-2641 (2017)
DOI: 10.1182/blood-2017-03-775569

62. Y. Dong, X. Zhao, X. Feng, Y. Zhou, X. Yan, Y. Zhang, J. Bu, D. Zhan, Y. Hayashi, Y. Zhang, Z. Xu, R. Huang, J. Wang, T. Zhao, Z. Xiao, Z. Ju, P. R. Andreassen, Q. F. Wang, W. Chen and G. Huang: SETD2 mutations confer chemoresistance in acute myeloid leukemia partly through altered cell cycle checkpoints. Leukemia (2019)
DOI: 10.1038/s41375-019-0456-2

63. I. K. Kim, J. N. McCutcheon, G. Rao, S. V. Liu, Y. Pommier, M. Skrzypski, Y. W. Zhang and G. Giaccone: Acquired SETD2 mutation and impaired CREB1 activation confer cisplatin resistance in metastatic non-small cell lung cancer. Oncogene, 38(2), 180-193 (2019)
DOI: 10.1038/s41388-018-0429-3

64. C. Jiang, C. He, Z. Wu, F. Li and J. Xiao: Corrigendum to 'Histone methyltransferase SETD2 regulates osteosarcoma cell growth and chemosensitivity by suppressing Wnt/beta-catenin signaling' (Biochem. Biophys. Res. Commun. Volume 502, Issue 3, 20 July 2018, Pages 382-388). Biochem Biophys Res Commun, 503(2), 1178 (2018)
DOI: 10.1016/j.bbrc.2018.06.123

65. W. Yang, J. Soares, P. Greninger, E. J. Edelman, H. Lightfoot, S. Forbes, N. Bindal, D. Beare, J. A. Smith, I. R. Thompson, S. Ramaswamy, P. A. Futreal, D. A. Haber, M. R. Stratton, C. Benes, U. McDermott and M. J. Garnett: Genomics of Drug Sensitivity in Cancer (GDSC): a resource for therapeutic biomarker discovery in cancer cells. Nucleic Acids Res, 41(Database issue), D955-61 (2013)
DOI: 10.1093/nar/gks1111

66. C. Feng, Y. Sun, G. Ding, Z. Wu, H. Jiang, L. Wang, Q. Ding and H. Wen: PI3Kbeta inhibitor TGX221 selectively inhibits renal cell carcinoma cells with both VHL and SETD2 mutations and links multiple pathways. Sci Rep, 5, 9465 (2015)
DOI: 10.1038/srep09465

Key Words: SETD2, H3K36me3, RNA Alternative Splicing, Tubulin Methylation, DNA Damage Repair, Progression and Prognostic biomarker, Review

Send correspondence to: Xiuli Liu, Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA, Tel: 352-265-7977, Fax: 352-627-9242, E-mail: xiuliliu@ufl.edu