DNMT3A loss drives a HIF-1-dependent synthetic lethality to HDAC6 inhibition in non-small cell lung cancer  

作　　者：Jiayu Zhang Yingxi Zhao Ruijuan Liang Xue Zhou Zhonghua Wang Cheng Yang Lingyue Gao Yonghao Zheng Hui Shao Yang Su Wei Cui Lina Jia Jingyu Yang Chunfu Wu Lihui Wang 

机构地区：[1]Department of Pharmacology,School of Life Science and Biopharmaceutics,Shenyang Pharmaceutical University,Shenyang 110016,China [2]bDepartment of Biochemistry and Molecular Biology,School of Medical Devices,Shenyang Pharmaceutical University,Shenyang 110016,China [3]Shengjing Hospital of China Medical University,Shenyang 110004,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第12期5219-5234,共16页药学学报（英文版）

基　　金：supported by grants from the National Natural Science Foundation of China(82272725 to Chunfu Wu,82073320 to Lihui Wang);“Xingliao Talents”Program of Liaoning Province(No.XLYC1902008 to Lihui Wang,China);Natural Science Foundation of Shenyang(22-315-6-11 to Lihui Wang,China).

摘　　要：DNMT3A encodes a DNA methyltransferase involved in development,cell differentiation,and gene transcription,which is mutated and aberrant-expressed in cancers.Here,we revealed that loss of DNMT3A promotes malignant phenotypes in lung cancer.Based on the epigenetic inhibitor library synthetic lethal screening,we found that small-molecule HDAC6 inhibitors selectively killed DNMT3A-defective NSCLC cells.Knockdown of HDAC6 by siRNAs reduced cell growth and induced apoptosis in DNMT3A-defective NSCLC cells.However,sensitive cells became resistant when DNMT3A was rescued.Furthermore,the selectivity to HDAC6 inhibition was recapitulated in mice,where an HDAC6 inhibitor retarded tumor growth established from DNMT3A-defective but not DNMT3A parental NSCLC cells.Mechanistically,DNMT3A loss resulted in the upregulation of HDAC6 through decreasing its promoter CpG methylation and enhancing transcription factor RUNX1 binding.Notably,our results indicated that HIF-1 pathway was activated in DNMT3A-defective cells whereas inactivated by HDAC6 inhibition.Knockout of HIF-1 contributed to the elimination of synthetic lethality between DNMT3A and HDAC6.Interestingly,HIF-1 pathway inhibitors could mimic the selective efficacy of HDAC6 inhibition in DNMT3A-defective cells.These results demonstrated HDAC6 as a HIF-1-dependent vulnerability of DNMT3A-defective cancers.Together,our findings identify HDAC6 as a potential HIF-1-dependent therapeutic target for the treatment of DNMT3A-defective cancers like NSCLC.

关 键 词：DNMT3A NSCLC Synthetic lethal HDAC6 HIF-1 

分 类 号：R734.2[医药卫生—肿瘤]