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
TABLE OF CONTENTS
- 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.
2. J. C. Black, C. Van Rechem and J. R. Whetstine: Histone lysine methylation dynamics: establishment, regulation, and biological impact.
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.
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.
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.
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.
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.
8. J. W. Edmunds, L. C. Mahadevan and A. L. Clayton: Dynamic histone H3 methylation during gene induction: HYPB/Setd2 mediates all H3K36 trimethylation.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
25. J. Li, G. Duns, H. Westers, R. Sijmons, A. van den Berg and K. Kok: SETD2: an epigenetic modifier with tumor suppressor functionality.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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?
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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: firstname.lastname@example.org