HDAC1,2 inhibition impairs EZH2-and BBAP- mediated DNA repair to overcome chemoresistance in EZH2 gain-of-function mutant diffuse large B-cell lymphoma

被引:36
作者
Johnson, Danielle P. [2 ]
Spitz, Gabriella S. [1 ]
Tharkar, Shweta [1 ]
Quayle, Steven N. [3 ]
Shearstone, Jeffrey R. [3 ]
Jones, Simon [3 ]
McDowell, Maria E. [1 ]
Wellman, Hannah [1 ]
Tyler, Jessica K. [4 ]
Cairns, Bradley R. [2 ]
Chandrasekharan, Mahesh B. [1 ]
Bhaskara, Srividya [1 ,2 ]
机构
[1] Univ Utah, Sch Med, Dept Radiat Oncol, Huntsman Canc Inst, Salt Lake City, UT 84112 USA
[2] Univ Utah, Sch Med, Dept Oncol Sci, Huntsman Canc Inst, Salt Lake City, UT USA
[3] Acetylon Pharmaceut Inc, Boston, MA USA
[4] Univ Texas MD Anderson Canc Ctr, Dept Biochem & Mol Biol, Houston, TX 77030 USA
关键词
epigenetics; DNA repair; HDAC1,2; chromatin; EZH2; HISTONE METHYLTRANSFERASE EZH2; NON-HODGKINS-LYMPHOMA; DOUBLE-STRAND BREAKS; DAMAGE RESPONSE; DEACETYLASE INHIBITORS; CHROMATIN-STRUCTURE; EPIGENETIC THERAPY; GENOME STABILITY; CANCER-CELLS; TUMOR-CELLS;
D O I
10.18632/oncotarget.3120
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Gain-of-function mutations in the catalytic site of EZH2 (Enhancer of Zeste Homologue 2), is observed in about 22% of diffuse large B-cell lymphoma (DLBCL) cases. Here we show that selective inhibition of histone deacetylase 1,2 (HDAC1,2) activity using a small molecule inhibitor causes cytotoxic or cytostatic effects in EZH2 gain-of-function mutant (EZH2(GOF)) DLBCL cells. Our results show that blocking the activity of HDAC1,2 increases global H3K27ac without causing a concomitant global decrease in H3K27me3 levels. Our data shows that inhibition of HDAC1,2 is sufficient to decrease H3K27me3 present at DSBs, decrease DSB repair and activate the DNA damage response in these cells. In addition to increased H3K27me3, we found that the EZH2GOF DLBCL cells overexpress another chemotherapy resistance factor - B-lymphoma and BAL-associated protein (BBAP). BBAP monoubiquitinates histone H4K91, a residue that is also subjected to acetylation. Our results show that selective inhibition of HDAC1,2 increases H4K91ac, decreases BBAP-mediated H4K91 monoubiquitination, impairs BBAP-dependent DSB repair and sensitizes the refractory EZH2GOF DLBCL cells to treatment with doxorubicin, a chemotherapy agent. Hence, selective HDAC1,2 inhibition provides a novel DNA repair mechanism-based therapeutic approach as it can overcome both EZH2- and BBAP-mediated DSB repair in the EZH2GOF DLBCL cells.
引用
收藏
页码:4863 / 4887
页数:25
相关论文
共 62 条
[1]   BAL is a novel risk-related gene in diffuse large B-cell lymphomas that enhances cellular migration [J].
Aguiar, RCT ;
Yakushijin, Y ;
Kharbanda, S ;
Salgia, R ;
Fletcher, JA ;
Shipp, MA .
BLOOD, 2000, 96 (13) :4328-4334
[2]  
[Anonymous], ADV HEMATOL
[3]   EZH2 Is Required for Germinal Center Formation and Somatic EZH2 Mutations Promote Lymphoid Transformation [J].
Beguelin, Wendy ;
Popovic, Relja ;
Teater, Matt ;
Jiang, Yanwen ;
Bunting, Karen L. ;
Rosen, Monica ;
Shen, Hao ;
Yang, Shao Ning ;
Wang, Ling ;
Ezponda, Teresa ;
Martinez-Garcia, Eva ;
Zhang, Haikuo ;
Zheng, Yupeng ;
Verma, Sharad K. ;
McCabe, Michael T. ;
Ott, Heidi M. ;
Van Aller, Glenn S. ;
Kruger, Ryan G. ;
Liu, Yan ;
McHugh, Charles F. ;
Scott, David W. ;
Chung, Young Rock ;
Kelleher, Neil ;
Shaknovich, Rita ;
Creasy, Caretha L. ;
Gascoyne, Randy D. ;
Wong, Kwok-Kin ;
Cerchietti, Leandro ;
Levine, Ross L. ;
Abdel-Wahab, Omar ;
Licht, Jonathan D. ;
Elemento, Olivier ;
Melnick, Ari M. .
CANCER CELL, 2013, 23 (05) :677-692
[4]   Deletion of histone deacetylase 3 reveals critical roles in S phase progression and DNA damage control [J].
Bhaskara, Srividya ;
Chyla, Brenda J. ;
Amann, Joseph M. ;
Knutson, Sarah K. ;
Cortez, David ;
Sun, Zu-Wen ;
Hiebert, Scott W. .
MOLECULAR CELL, 2008, 30 (01) :61-72
[5]   Histone deacetylases 1 and 2 maintain S-phase chromatin and DNA replication fork progression [J].
Bhaskara, Srividya ;
Jacques, Vincent ;
Rusche, James R. ;
Olson, Eric N. ;
Cairns, Bradley R. ;
Chandrasekharan, Mahesh B. .
EPIGENETICS & CHROMATIN, 2013, 6
[6]   Role for histone deacetylase 3 in maintenance of genome stability [J].
Bhaskara, Srividya ;
Hiebert, Scott W. .
CELL CYCLE, 2011, 10 (05) :727-728
[7]   Hdac3 Is Essential for the Maintenance of Chromatin Structure and Genome Stability [J].
Bhaskara, Srividya ;
Knutson, Sarah K. ;
Jiang, Guochun ;
Chandrasekharan, Mahesh B. ;
Wilson, Andrew J. ;
Zheng, Siyuan ;
Yenamandra, Ashwini ;
Locke, Kimberly ;
Yuan, Jia-ling ;
Bonine-Summers, Alyssa R. ;
Wells, Christina E. ;
Kaiser, Jonathan F. ;
Washington, M. Kay ;
Zhao, Zhongming ;
Wagner, Florence F. ;
Sun, Zu-Wen ;
Xia, Fen ;
Holson, Edward B. ;
Khabele, Dineo ;
Hiebert, Scott W. .
CANCER CELL, 2010, 18 (05) :436-447
[8]   EZH2 Y641 mutations in follicular lymphoma [J].
Boedoer, C. ;
O'Riain, C. ;
Wrench, D. ;
Matthews, J. ;
Iyengar, S. ;
Tayyib, H. ;
Calaminici, M. ;
Clear, A. ;
Iqbal, S. ;
Quentmeier, H. ;
Drexler, H. G. ;
Montoto, S. ;
Lister, A. T. ;
Gribben, J. G. ;
Matolcsy, A. ;
Fitzgibbon, J. .
LEUKEMIA, 2011, 25 (04) :726-729
[9]   HDAC inhibitors induce tumor-cell-selective pro-apoptotic transcriptional responses [J].
Bolden, J. E. ;
Shi, W. ;
Jankowski, K. ;
Kan, C-Y ;
Cluse, L. ;
Martin, B. P. ;
MacKenzie, K. L. ;
Smyth, G. K. ;
Johnstone, R. W. .
CELL DEATH & DISEASE, 2013, 4 :e519-e519
[10]   EZH2 Inhibitor Efficacy in Non-Hodgkin's Lymphoma Does Not Require Suppression of H3K27 Monomethylation [J].
Bradley, William D. ;
Arora, Shilpi ;
Busby, Jennifer ;
Balasubramanian, Srividya ;
Gehling, Victor S. ;
Nasveschuk, Christopher G. ;
Vaswani, Rishi G. ;
Yuan, Chih-Chi ;
Hatton, Charlie ;
Zhao, Feng ;
Williamson, Kaylyn E. ;
Iyer, Priyadarshini ;
Mendez, Jacqui ;
Campbell, Robert ;
Cantone, Nico ;
Garapaty-Rao, Shivani ;
Audia, James E. ;
Cook, Andrew S. ;
Dakin, Les A. ;
Albrecht, Brian K. ;
Harmange, Jean-Christophe ;
Daniels, Danette L. ;
Cummings, Richard T. ;
Bryant, Barbara M. ;
Normant, Emmanuel ;
Trojer, Patrick .
CHEMISTRY & BIOLOGY, 2014, 21 (11) :1463-1475