KMT2D Deficiency Impairs Super-Enhancers to Confer a Glycolytic Vulnerability in Lung Cancer

被引：164

作者：

Alam, Hunain ^{[1
]}

Tang, Ming ^{[2
]}

Maitituoheti, Mayinuer ^{[2
]}

Dhar, Shilpa S. ^{[1
]}

Kumar, Manish ^{[1
]}

Han, Chae Young ^{[1
]}

Ambati, Chandrashekar R. ^{[3
,4
]}

Amin, Samir B. ^{[2
]}

Gu, Bingnan ^{[1
]}

Chen, Tsai-Yu ^{[1
]}

Lin, Yu-Hsi ^{[5
]}

Chen, Jichao ^{[6
]}

Muller, Florian L. ^{[5
]}

Putluri, Nagireddy ^{[3
,4
]}

Flores, Elsa R. ^{[7
,8
]}

DeMayo, Francesco J. ^{[9
]}

Baseler, Laura ^{[10
,11
]}

Rai, Kunal ^{[2
]}

Lee, Min Gyu ^{[1
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, 1515 Holcombe Blvd, Houston, TX 77030 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, 1901 East Rd, Houston, TX 77054 USA

[3] Baylor Coll Med, Adv Technol Core, Houston, TX 77030 USA

[4] Baylor Coll Med, Dept Mol & Cell Biol, Houston, TX 77030 USA

[5] Univ Texas MD Anderson Canc Ctr, Dept Canc Syst Imaging, 1881 East Rd, Houston, TX 77054 USA

[6] Univ Texas MD Anderson Canc Ctr, Dept Pulm Med, Houston, TX 77030 USA

[7] H Lee Moffitt Canc Ctr & Res Inst, Dept Mol Oncol, 12902 Magnolia Dr, Tampa, FL 33612 USA

[8] H Lee Moffitt Canc Ctr & Res Inst, Canc Biol & Evolut Program, 12902 Magnolia Dr, Tampa, FL 33612 USA

[9] NIEHS, Reprod & Dev Biol Lab, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA

[10] Univ Texas MD Anderson Canc Ctr, Dept Vet Med & Surg, 1515 Holcombe Blvd, Houston, TX 77030 USA

[11] NAMSA, 6750 Wales Rd, Northwood, OH 43619 USA

来源：

CANCER CELL | 2020年 / 37卷 / 04期

基金：

美国国家卫生研究院;

关键词：

R/BIOCONDUCTOR PACKAGE; GROWTH; P53; TRANSCRIPTION; DISRUPTION; INHIBITION; EXPRESSION; KINASE; MODELS; CELLS;

D O I：

10.1016/j.ccell.2020.03.005

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Epigenetic modifiers frequently harbor loss-of-function mutations in lung cancer, but their tumor-suppressive roles are poorly characterized. Histone methyltransferase KMT2D (a COMPASS-like enzyme, also called MLL4) is among the most highly inactivated epigenetic modifiers in lung cancer. Here, we show that lung-specific loss of Kmt2d promotes lung tumorigenesis in mice and upregulates pro-tumorigenic programs, including glycolysis. Pharmacological inhibition of glycolysis preferentially impedes tumorigenicity of human lung cancer cells bearing KMT2D-inactivating mutations. Mechanistically, Kmt2d loss widely impairs epigenomic signals for super-enhancers/enhancers, including the super-enhancer for the circadian rhythm repressor Per2. Loss of Kmt2d decreases expression of PER2, which regulates multiple glycolytic genes. These findings indicate that KMT2D is a lung tumor suppressor and that KMT2D deficiency confers a therapeutic vulnerability to glycolytic inhibitors.

引用

页码：599 / +

页数：26

共 99 条

[1] HP1γ Promotes Lung Adenocarcinoma by Downregulating the Transcription-Repressive Regulators NCOR2 and ZBTB7A [J].

Alam, Hunain ;

Li, Na ;

Dhar, Shilpa S. ;

Wu, Sarah J. ;

Lv, Jie ;

Chen, Kaifu ;

Flores, Elsa R. ;

Baseler, Laura ;

Lee, Min Gyu .

CANCER RESEARCH, 2018, 78 (14) :3834-3848

[2] The diverse functions of Dot1 and H3K79 methylation [J].

Anh Tram Nguyen ;

Zhang, Yi .

GENES & DEVELOPMENT, 2011, 25 (13) :1345-1358

[3] High-resolution profiling of histone methylations in the human genome [J].

Barski, Artern ;

Cuddapah, Suresh ;

Cui, Kairong ;

Roh, Tae-Young ;

Schones, Dustin E. ;

Wang, Zhibin ;

Wei, Gang ;

Chepelev, Iouri ;

Zhao, Keji .

CELL, 2007, 129 (04) :823-837

[4] Circadian Integration of Metabolism and Energetics [J].

Bass, Joseph ;

Takahashi, Joseph S. .

SCIENCE, 2010, 330 (6009) :1349-1354

[5] Histone deacetylase inhibition rescues structural and functional brain deficits in a mouse model of Kabuki syndrome [J].

Bjornsson, Hans T. ;

Benjamin, Joel S. ;

Zhang, Li ;

Weissman, Jacqueline ;

Gerber, Elizabeth E. ;

Chen, Yi-Chun ;

Vaurio, Rebecca G. ;

Potter, Michelle C. ;

Hansen, Kasper D. ;

Dietz, Harry C. .

SCIENCE TRANSLATIONAL MEDICINE, 2014, 6 (256)

[6]

Brawer Michael K, 2005, Rev Urol, V7 Suppl 7, pS21

[7] Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas [J].

Campbell, Joshua D. ;

Alexandrov, Anton ;

Kim, Jaegil ;

Wala, Jeremiah ;

Berger, Alice H. ;

Pedamallu, Chandra Sekhar ;

Shukla, Sachet A. ;

Guo, Guangwu ;

Brooks, Angela N. ;

Murray, Bradley A. ;

Imielinski, Marcin ;

Hu, Xin ;

Ling, Shiyun ;

Akbani, Rehan ;

Rosenberg, Mara ;

Cibulskis, Carrie ;

Ramachandran, Aruna ;

Collisson, Eric A. ;

Kwiatkowski, David J. ;

Lawrence, Michael S. ;

Weinstein, John N. ;

Verhaak, Roel G. W. ;

Wu, Catherine J. ;

Hammerman, Peter S. ;

Cherniack, Andrew D. ;

Getz, Gad ;

Artyomov, Maxim N. ;

Schreiber, Robert ;

Govindan, Ramaswamy ;

Meyerson, Matthew .

NATURE GENETICS, 2016, 48 (06) :607-+

[8]

Cancer Genome Atlas Research Network, 2018, Nature, V559, pE12, DOI [10.1038/nature13385, 10.1038/s41586-018-0228-6]

[9] α-enolase: a promising therapeutic and diagnostic tumor target [J].

Capello, Michela ;

Ferri-Borgogno, Sammy ;

Cappello, Paola ;

Novelli, Francesco .

FEBS JOURNAL, 2011, 278 (07) :1064-1074

[10] The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data [J].

Cerami, Ethan ;

Gao, Jianjiong ;

Dogrusoz, Ugur ;

Gross, Benjamin E. ;

Sumer, Selcuk Onur ;

Aksoy, Buelent Arman ;

Jacobsen, Anders ;

Byrne, Caitlin J. ;

Heuer, Michael L. ;

Larsson, Erik ;

Antipin, Yevgeniy ;

Reva, Boris ;

Goldberg, Arthur P. ;

Sander, Chris ;

Schultz, Nikolaus .

CANCER DISCOVERY, 2012, 2 (05) :401-404

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