Repressing MYC by targeting BET synergizes with selective inhibition of PI3K alpha against B cell lymphoma

doi:10.1016/j.canlet.2021.10.022

	Repressing MYC by targeting BET synergizes with selective inhibition of PI3K alpha against B cell lymphoma
	Chen, Zi-qi 1; Cao, Zhe-rui 2; Wang, Yi 1; Zhang, Xi 1; Xu, Lan 1; Wang, Yu-xiang 1; Chen, Yi 1; Yang, Chun-hao 3; Ding, Jian 4; Meng, Ling-hua 1,2
刊名	CANCER LETTERS
	2022
卷号	524 页码:206-218
关键词	CYH33 MYC P300 BET B cell lymphoma PI3K
ISSN号	0304-3835
DOI	10.1016/j.canlet.2021.10.022
通讯作者	Ding, Jian(jding@simm.ac.cn) ; Meng, Ling-hua(lhmeng@simm.ac.cn)
英文摘要	Phosphatidylinositol 3-kinase (PI3K) 6-specific inhibitors have been approved for the therapy of certain types of B cell lymphoma (BCL). However, their clinical use is limited by the substantial toxicity and lack of efficacy in other types of BCL. Emerging evidence indicates that PI3K alpha plays important roles in the progression of B cell lymphoma. In this study, we revealed that PI3K alpha was important for the PI3K signaling and proliferation in BCL cells. A novel clinical PI3K alpha-selective inhibitor CYH33 possessed superior activity against BCL compared to the marketed PI3K alpha-selective inhibitor Alpelisib and PI3K6-selective inhibitor Idelalisib. Though CYH33 was able to inhibit PI3K/AKT signaling in tested BCL cells, differential activity against proliferation was observed. Transcriptome profiling revealed that CYH33 down-regulated "MYC-targets" gene set in sensitive but not resistant cells. CYH33 inhibited c-MYC transcription in sensitive cells, which was attributed to a decrease in acetylated H3 bound to the promoter and super-enhancer region of c-MYC. Accordingly, CYH33 treatment resulted in phosphorylation and proteasomal degradation of the histone acetyltransferase p300. An unbiased screening with drugs approved or in clinical trials for the therapy of BCL identified that the clinical BET (Bromodomain and Extra Terminal domain) inhibitor OTX015 significantly potentiated the activity of CYH33 against BCL in vitro and in vivo, which was associated with enhanced inhibition on c-MYC expression and induction of cell cycle arrest and apoptosis. Our findings provide the rationale of combined CYH33 with BET inhibitors for the therapy of B cell lymphoma.
WOS关键词	SOMATIC MUTATIONS ; EXPRESSION ; PI3K ; ACTIVATION ; APOPTOSIS ; GROWTH ; CANCER ; DEATH ; DLBCL ; P300
WOS研究方向	Oncology
语种	英语
出版者	ELSEVIER IRELAND LTD
WOS记录号	WOS:000712461200001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/298781]
专题	中国科学院上海药物研究所
通讯作者	Ding, Jian; Meng, Ling-hua
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, Shanghai, Peoples R China 2.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Chen, Zi-qi,Cao, Zhe-rui,Wang, Yi,et al. Repressing MYC by targeting BET synergizes with selective inhibition of PI3K alpha against B cell lymphoma[J]. CANCER LETTERS,2022,524:206-218.
APA	Chen, Zi-qi.,Cao, Zhe-rui.,Wang, Yi.,Zhang, Xi.,Xu, Lan.,...&Meng, Ling-hua.(2022).Repressing MYC by targeting BET synergizes with selective inhibition of PI3K alpha against B cell lymphoma.CANCER LETTERS,524,206-218.
MLA	Chen, Zi-qi,et al."Repressing MYC by targeting BET synergizes with selective inhibition of PI3K alpha against B cell lymphoma".CANCER LETTERS 524(2022):206-218.