Research advances in mechanisms of super-enhancers-driven oncogenesis

doi:10.3969/j.issn.1674-8115.2021.10.017

Abstract

Abstract:

Transcriptional dysregulation is one of the core mechanisms of tumorigenesis. Recently, the term "super-enhancer" has been introduced to describe a hyperactive regulatory domain which comprises a complex array of sequence elements that are critical to maintain the identity of tumor cells and promot oncogenic transcription. Super-enhancers are highly occupied by transcriptional factors, co-activators and histone modifications. Cooperative interactions amongst these components make super-enhancers have higher transcriptional activity than typical enhancers. This article reviews basic structural and functional characteristics of super-enhancers, formation of the phase-separated condensates, the mechanisms of super-enhancer-driven oncogenesis, and the formation and significance of topologically associating domains.

Key words: super-enhancers (SEs), transcriptional regulation, cancer, phase-separated condensate, topologically associating domain

CLC Number:

R394.3

Peng GU, Xing SUN. Research advances in mechanisms of super-enhancers-driven oncogenesis[J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(10): 1378-1383.

TrendMD

References 63

1	Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation[J]. Cell, 2011, 144(5): 646-674.
2	Bradner JE, Hnisz D, Young RA. Transcriptional addiction in cancer[J]. Cell, 2017, 168(4): 629-643.
3	Lee TI, Young RA. Transcriptional regulation and its misregulation in disease[J]. Cell, 2013, 152(6): 1237-1251.
4	Benoist C, Chambon P. In vivo sequence requirements of the SV40 early promotor region[J]. Nature, 1981, 290(5804): 304-310.
5	孙长斌, 张曦. 超级增强子研究进展[J]. 遗传, 2016, 38(12): 1056-1068.
6	Bulger M, Groudine M. Functional and mechanistic diversity of distal transcription enhancers[J]. Cell, 2011, 144(3): 327-339.
7	Sur I, Taipale J. The role of enhancers in cancer[J]. Nat Rev Cancer, 2016, 16(8): 483-493.
8	Fukaya T, Lim B, Levine M. Enhancer control of transcriptional bursting[J]. Cell, 2016, 166(2): 358-368.
9	Whyte WA, Orlando David A, Hnisz D, et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes[J]. Cell, 2013, 153(2): 307-319.
10	ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome[J]. Nature, 2012, 489(7414): 57-74.
11	Calo E, Wysocka J. Modification of enhancer chromatin: what, how, and why?[J]. Mol Cell, 2013, 49(5): 825-837.
12	Sengupta S, George RE. Super-enhancer-driven transcriptional dependencies in cancer[J]. Trends Cancer, 2017, 3(4): 269-281.
13	Ramachandran S, Henikoff S. Transcriptional regulators compete with nucleosomes post-replication[J]. Cell, 2016, 165(3): 580-592.
14	Gross DS, Garrard WT. Nuclease hypersensitive sites in chromatin[J]. Annu Rev Biochem, 1988, 57: 159-197.
15	Hnisz D, Abraham BJ, Lee TI, et al. Super-enhancers in the control of cell identity and disease[J]. Cell, 2013,155(4): 934-947.
16	Hnisz D, Schuijers J, Lin CY, et al. Convergence of developmental and oncogenic signaling pathways at transcriptional super-enhancers[J]. Mol Cell, 2015, 58(2): 362-370.
17	Deng R, Huang JH, Wang Y, et al. Disruption of super-enhancer-driven tumor suppressor gene RCAN1.4 expression promotes the malignancy of breast carcinoma[J]. Mol Cancer, 2020, 19(1): 122.
18	Lin CY, Erkek S, Tong Y, et al. Active medulloblastoma enhancers reveal subgroup-specific cellular origins[J]. Nature, 2016, 530(7588): 57-62.
19	Levine M, Cattoglio C, Tjian R. Looping back to leap forward: transcription enters a new era[J]. Cell, 2014, 157(1): 13-25.
20	Nozawa K, Schneider TR, Cramer P. Core Mediator structure at 3.4 Å extends model of transcription initiation complex[J]. Nature, 2017, 545(7653): 248-251.
21	Kagey MH, Newman JJ, Bilodeau S, et al. Mediator and cohesin connect gene expression and chromatin architecture[J]. Nature, 2010, 467(7314): 430-435.
22	Hnisz D, Shrinivas K, Young RA, et al. A phase separation model for transcriptional control[J]. Cell, 2017, 169(1): 13-23.
23	Shin Y, Brangwynne CP. Liquid phase condensation in cell physiology and disease[J]. Science, 2017, 357(6357): eaaf4382.
24	Brangwynne CP, Eckmann CR, Courson DS, et al. Germline P granules are liquid droplets that localize by controlled dissolution/condensation[J]. Science, 2009, 324(5935): 1729-1732.
25	Sabari BR, Dall'Agnese A, Boija A, et al. Coactivator condensation at super-enhancers links phase separation and gene control[J]. Science, 2018, 361(6400):eaar3958.
26	Boija A, Klein IA, Sabari BR, et al. Transcription factors activate genes through the phase-separation capacity of their activation domains[J]. Cell, 2018, 175(7): 1842-1855.e16.
27	Lu H, Yu D, Hansen AS, et al. Phase-separation mechanism for C-terminal hyperphosphorylation of RNA polymerase II[J]. Nature, 2018, 558(7709):318-323.
28	Cook PR, Marenduzzo D. Transcription-driven genome organization: a model for chromosome structure and the regulation of gene expression tested through simulations[J]. Nucleic Acids Res, 2018, 46(19): 9895-9906.
29	Filippakopoulos P, Qi J, Picaud S, et al. Selective inhibition of BET bromodomains[J]. Nature, 2010, 468(7327): 1067-1073.
30	Kwiatkowski N, Zhang T, Rahl PB, et al. Targeting transcription regulation in cancer with a covalent CDK7 inhibitor[J]. Nature, 2014, 511(7511):616-620.
31	Chapuy B, McKeown MR, Lin CY, et al. Discovery and characterization of super-enhancer-associated dependencies in diffuse large B cell lymphoma[J]. Cancer Cell, 2013, 24(6): 777-790.
32	Bhagwat AS, Roe JS, Mok BYL, et al. BET bromodomain inhibition releases the mediator complex from select Cis-regulatory elements[J]. Cell Rep, 2016, 15(3): 519-530.
33	Chipumuro E, Marco E, Christensen CL, et al. CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer[J]. Cell, 2014, 159(5): 1126-1139.
34	Wang Y, Zhang T, Kwiatkowski N, et al. CDK7-dependent transcriptional addiction in triple-negative breast cancer[J]. Cell, 2015, 163(1): 174-186.
35	Faivre EJ, McDaniel KF, Albert DH, et al. Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer[J]. Nature, 2020, 578(7794): 306-310.
36	McDaniel KF, Wang L, Soltwedel T, et al. Discovery of N-(4-(2,4-Difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)ethanesulfonamide (ABBV-075/Mivebresib), a potent and orally available bromodomain and extraterminal domain (BET) family bromodomain inhibitor[J]. J Med Chem, 2017, 60(20): 8369-8384.
37	Pelish HE, Liau BB, Nitulescu II, et al. Mediator kinase inhibition further activates super-enhancer-associated genes in AML[J]. Nature, 2015, 526(7572): 273-276.
38	Zhang C, Wei S, Sun WP, et al. Super-enhancer-driven AJUBA is activated by TCF4 and involved in epithelial-mesenchymal transition in the progression of hepatocellular carcinoma[J]. Theranostics, 2020, 10(20): 9066-9082.
39	Nguyen TTT, Zhang Y, Shang E, et al. HDAC inhibitors elicit metabolic reprogramming by targeting super-enhancers in glioblastoma models[J]. J Clin Invest, 2020, 130(7): 3699-3716.
40	Betancur PA, Abraham BJ, Yiu YY, et al. A CD47-associated super-enhancer links pro-inflammatory signalling to CD47 upregulation in breast cancer[J]. Nat Commun, 2017, 8:14802.
41	Shang E, Nguyen TTT, Shu C, et al. Epigenetic targeting of Mcl-1 is synthetically lethal with Bcl-xL/Bcl-2 inhibition in model systems of glioblastoma[J]. Cancers (Basel), 2020, 12(8): 2137.
42	Suzuki HI, Young RA, Sharp PA. Super-enhancer-mediated RNA processing revealed by integrative MicroRNA network analysis[J]. Cell, 2017, 168(6): 1000-1014.e15.
43	Han J, Meng J, Chen S, et al. YY1 Complex promotes quaking expression via super-enhancer binding during EMT of hepatocellular carcinoma[J]. Cancer Res, 2019, 79(7): 1451-1464.
44	Thandapani P. Super-enhancers in cancer[J]. Pharmacol Ther, 2019, 199: 129-138.
45	Mansour MR, Abraham BJ, Anders L, et al. Oncogene regulation. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element[J]. Science, 2014, 346(6215): 1373-1377.
46	Oldridge DA, Wood AC, Weichert-Leahey N, et al. Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism[J]. Nature, 2015, 528(7582): 418-421.
47	Kandaswamy R, Sava GP, Speedy HE, et al. Genetic predisposition to chronic lymphocytic leukemia is mediated by a BMF super-enhancer polymorphism[J]. Cell Rep, 2016, 16(8): 2061-2067.
48	Zhang X, Choi PS, Francis JM, et al. Identification of focally amplified lineage-specific super-enhancers in human epithelial cancers[J]. Nat Genet, 2016, 48(2): 176-182.
49	Herranz D, Ambesi-Impiombato A, Palomero T, et al. A NOTCH1-driven MYC enhancer promotes T cell development, transformation and acute lymphoblastic leukemia[J]. Nat Med, 2014, 20(10): 1130-1137.
50	Drier Y, Cotton MJ, Williamson KE, et al. An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma[J]. Nat Genet, 2016, 48(3): 265-272.
51	Northcott PA, Lee C, Zichner T, et al. Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma[J]. Nature, 2014, 511(7510): 428-434.
52	Kaiser VB, Semple CA. When TADs go bad: chromatin structure and nuclear organisation in human disease[J]. F1000Res, 2017, 6: 314.
53	Dixon JR, Gorkin DU, Ren B. Chromatin domains: the unit of chromosome organization[J]. Mol Cell, 2016, 62(5): 668-680.
54	Dixon JR, Selvaraj S, Yue F, et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions[J]. Nature, 2012, 485(7398): 376-380.
55	Dowen JM, Fan ZP, Hnisz D, et al. Control of cell identity genes occurs in insulated neighborhoods in mammalian chromosomes[J]. Cell, 2014, 159(2): 374-387.
56	Katainen R, Dave K, Pitkanen E, et al. CTCF/cohesin-binding sites are frequently mutated in cancer[J]. Nat Genet, 2015, 47(7): 818-821.
57	Hnisz D, Day DS, Young RA. Insulated neighborhoods: structural and functional units of mammalian gene control[J]. Cell, 2016, 167(5): 1188-1200.
58	Weischenfeldt J, Dubash T, Drainas AP, et al. Pan-cancer analysis of somatic copy-number alterations implicates IRS4 and IGF2 in enhancer hijacking[J]. Nat Genet, 2017, 49(1): 65-74.
59	Dixon JR, Xu J, Dileep V, et al. Integrative detection and analysis of structural variation in cancer genomes[J]. Nat Genet, 2018, 50(10): 1388-1398.
60	Taberlay PC, Achinger-Kawecka J, Lun AT, et al. Three-dimensional disorganization of the cancer genome occurs coincident with long-range genetic and epigenetic alterations[J]. Genome Res, 2016, 26(6): 719-731.
61	Flavahan WA, Drier Y, Liau BB, et al. Insulator dysfunction and oncogene activation in IDH mutant gliomas[J]. Nature, 2016, 529(7584):110-114.
62	Buenrostro JD, Giresi PG, Zaba LC, et al. Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position[J]. Nat Methods, 2013, 10(12): 1213-1218.
63	Kaya-Okur HS, Wu SJ, Codomo CA, et al. CUT&Tag for efficient epigenomic profiling of small samples and single cells[J]. Nat Commun, 2019, 10(1): 1930.

[1]	PAERHATI Nadina, ZHANG Pengshan, XU Yitian, CHEN Yunqi, HUANG Chen. Construction of a truncated cylindromatosis tumor suppressor deubiquitinase plasmid and its regulation of the phenotypes of gastric cancer cells [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(9): 1149-1160.
[2]	WANG Jingyi, DENG Jiali, ZHU Yi, DING Xinyi, GUO Jiajing, WANG Zhongling. Experimental study on novel pH-responsive manganese-based nanoprobes for ferroptosis and magnetic resonance imaging in breast cancer [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(9): 1183-1193.
[3]	YIN Ziming, WANG Rongqin, YANG Ziyi, LIU Yingbin, CHEN Tao, SHU Yijun, GONG Wei. Graph neural network-based auxiliary diagnostic model for gallbladder cancer on CT imaging [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(9): 1221-1231.
[4]	JIANG Yi, HUANG Chenhao, LI Zhiliang, WU Junwei, ZHAO Ren, ZHANG Tao. Effect of preoperative chemotherapy combined with immunotherapy in a colorectal cancer patient with KRAS mutation [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(9): 1256-1260.
[5]	HUANG Xin, LIU Jiahui, YE Jingwen, QIAN Wenli, XU Wanxing, WANG Lin. Development and clinical application of a machine learning-driven model for metabolite-based diagnosis of small cell lung cancer [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(8): 1009-1016.
[6]	ZHANG Yuqin, AIHEMAITI Yilixiati, WANG Yanli, YANG Zhi, HUANG Jian. Ubiquitination and degradation of RPTPα mediated by MARCH9 [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(8): 957-968.
[7]	AIMAITI Muerzhate, ZHANG Yeqian, LIU Tao, BAI Long, ZHANG Haoyu, NI Bo, GUAN Yujing, WANG Shuchang, GU Jiayi, ZHU Chunchao, XIA Xiang, ZHANG Zizhen. A comparative analysis of the short-term efficacy of robotic and laparoscopic proximal gastrectomy combined with double-flap anastomosis in the treatment of early upper gastric cancer [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(7): 874-882.
[8]	WANG Rui, YUAN Ying, TAO Xiaofeng. Application value of synthetic magnetic resonance imaging in predicting cervical lymph node metastasis of oral cancer [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(7): 900-909.
[9]	YANG Na, LIU Junli, BAI Jing, YANG Siyi, HAN Jiming, ZHANG Huahua. HENMT1 promotes the proliferation and migration of gastric cancer by activating the PI3K-AKT-mTOR signaling pathway [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(6): 717-726.
[10]	TANG Kairan, FENG Chengling, HAN Bangmin. Integrated single-cell and transcriptome sequencing to construct a prognostic model of M2 macrophage-related genes in prostate cancer [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(5): 549-561.
[11]	MAO Chenzhou, ZHANG Ruiyun, CHEN Haige, YIN Fangfei, ZUO Xiaolei. Framework nucleic acid-based linear amplification platform for sensitive detection of bladder cancer-related miRNAs [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(3): 253-260.
[12]	DENG Jiali, GUO Jiajing, WANG Jingyi, DING Xinyi, ZHU Yi, WANG Zhongling. Self -assembled drug -loaded nanoprobes for pyroptosis sensitization and chemical exchange saturation transfer imaging in breast cancer [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(3): 271-281.
[13]	CHEN Jiaying, CHU Yimin, PENG Haixia. Study on prediction model and influencing factors of progression-free survival in colorectal cancer [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(3): 324-334.
[14]	ZOU Peichen, LIU Hongyu, AIHEMAITI· Ayinazhaer, ZHU Liang, TANG Yabin, LEI Huimin. Metabolic profiling of lung cancer cells with acquired resistance to sotorasib [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(2): 138-149.
[15]	CHEN Yongyu, HUANG Yiren, CHEN Zheyi, ZHOU Bingqian, CHEN Shiyu, ZHENG Yingxia. Expression of serpin family E member 1 in gastric cancer and its mechanisms in promoting gastric cancer [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(2): 150-160.