Inhibition of BETs prevents heat shock-induced cell death via upregulating HSPs in SV40 large T antigen transfected cells

다국어 초록 (Multilingual Abstract)

Background: Heat shock response is a protected mechanism against environmental changes for the organism, which must be tightly regulated. Bromodomain and extra terminal-containing protein family (BETs) regulate numerous gene expression in many physiological and pathological conditions, including viral infection. SV40 is considered as a highly human disease-associated virus.
Objective: We aimed to explore whether BETs play a role in heat shock in SV40 large T antigen transfected cells.
Methods: SV40LTA was transfected in HeLa cells using the Lipofectamine 8000. BETs inhibitor JQ1 and I-BET-762 was employed to treat transfected cells and HEK-293 T cells. Heat shock treatment was performed to determine the effect of JQ1 and I-BET-762 on these cells. Western blot and quantitative RT-PCR were carried out to assess the expression of HSP70 and other HSPs.
Results: We found that inhibition of BETs by JQ1 and I-BET-762 protects cells from heat shock-induced death in HEK293T cells. Both JQ1 and I-BET-762 induce the expression of HSPs and HSF1 in HEK-293 T cells. However, neither JQ1 nor I-BET-762 fail to induce the expression of HSPs in either HeLa or HBL-1 cells. When SV40 large T antigen was transfected into HeLa cells, the induction of HSP70 expressing and the protection of heat shock-induced cell death are reproduced by JQ1 and IBET treatment in these transfected cells.
Conclusions: Inhibition of BETs by JQ1 and I-BET-762 prevents heat shock-induced cell death via upregulating HSPs in SV40 large T antigen transfected cells. Our data indicate a novel function of BETs in SV40 large T antigen transformed cells, affecting HSPs and HSF1 as well as its function on heat shock response.

참고문헌 (Reference)

1 Richter K, "The heat shock response : life on the verge of death" 40 : 253-266, 2010

2 Hussong M, "The bromodomain protein BRD4 regulates splicing during heat shock" 45 : 382-394, 2017

3 Taniguchi Y, "The bromodomain and extra-terminal domain(BET)family : functional anatomy of BET paralogous proteins" 17 (17): 1849-, 2016

4 Bid HK, "The bromodomain BET inhibitor JQ1 suppresses tumor angiogenesis in models of childhood sarcoma" 15 : 1018-1028, 2016

5 Dawson MA, "Targeting epigenetic readers in cancer" 367 : 647-657, 2012

6 Filippakopoulos P, "Targeting bromodomains : epigenetic readers of lysine acetylation" 13 : 337-356, 2014

7 Loven J, "Selective inhibition of tumor oncogenes by disruption of super-enhancers" 153 : 320-334, 2013

8 Gazdar AF, "SV40 and human tumours : myth, association or causality?" 2 : 957-964, 2002

9 Anckar J, "Regulation of HSF1 function in the heat stress response : implications in aging and disease" 80 : 1089-1115, 2011

10 Mao RF, "OLA1 protects cells in heat shock by stabilizing HSP70" 4 : e491-, 2013

11 Mayer MP, "Hsp70 chaperones : cellular functions and molecular mechanism" 62 : 670-684, 2005

12 Yaglom JA, "High levels of heat shock protein Hsp72 in cancer cells suppress default senescence pathways" 67 : 2373-2381, 2007

13 Mukhopadhyay I, "Heat shock response : hsp70 in environmental monitoring" 17 : 249-254, 2003

14 Akerfelt M, "Heat shock factors : integrators of cell stress, development and lifespan" 11 : 545-555, 2010

15 Sorger PK, "Heat shock factor and the heat shock response" 65 : 363-366, 1991

16 Dai C, "Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis" 130 : 1005-1018, 2007

17 Asea A, "HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine" 6 : 435-442, 2000

18 Moriniere J, "Cooperative binding of two acetylation marks on a histone tail by a single bromodomain" 461 : 664-668, 2009

19 de Nadal E, "Controlling gene expression in response to stress" 12 : 833-845, 2011

20 Wang X, "Bromodomain protein Brd4 plays a key role in Merkel cell polyomavirus DNA replication" 8 : e1003021-, 2012

21 Col E, "Bromodomain factors of BET family are new essential actors of pericentric heterochromatin transcriptional activation in response to heat shock" 7 : 5418-, 2017

22 Wang CY, "Beating the odds : BETs in disease" 40 : 468-479, 2015

23 Wu SY, "BRD4 phosphorylation regulates HPV E2-mediated viral transcription, origin replication, and cellular MMP-9 expression" 16 : 1733-1748, 2016

24 Borck PC, "BET epigenetic reader proteins in cardiovascular transcriptional programs" 126 : 1190-1208, 2020

25 Delmore JE, "BET bromodomain inhibition as a therapeutic strategy to target c-Myc" 146 : 904-917, 2011