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

文献类型：期刊论文

作者Chen, Zi-qi1; Cao, Zhe-rui2; Wang, Yi1; Zhang, Xi1; Xu, Lan1; Wang, Yu-xiang1; Chen, Yi1; Yang, Chun-hao3; Ding, Jian4; Meng, Ling-hua1,2
刊名CANCER LETTERS
出版日期2022
卷号524页码:206-218
关键词CYH33 MYC P300 BET B cell lymphoma PI3K
ISSN号0304-3835
DOI10.1016/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
WOS记录号WOS:000712461200001
出版者ELSEVIER IRELAND LTD
源URL[http://119.78.100.183/handle/2S10ELR8/298781]  
专题新药研究国家重点实验室
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.

入库方式： OAI收割

来源：上海药物研究所

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