The SIRT7-mediated deacetylation of CHD1L amplifies HIF-2α-dependent signal that drives renal cell carcinoma progression and sunitinib resistance

Cell & Bioscience

Research

Wei Wang¹  Juan Jin²  Jie Li³  Qunyi Li⁴  Li Chen⁵  Hongchao He⁶  Jie Cheng⁷  Jian Zhou⁷ 

[1] Department of Clinical Laboratory, Lianshui County People’s Hospital, 223400, Huai’an, China;Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), 310000, Hangzhou, Zhejiang, China;Department of Oncology, Second Affiliated Hospital, Nanjing Medical University, 210000, Nanjing, China;Department of Pharmacy, Huashan Hospital, Fudan University, 200040, Shanghai, China;Department of Pharmacy, Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University, 200031, Shanghai, China;Department of Urology, Shanghai Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 200025, Shanghai, China;Zhongshan Hospital, Fudan University, 200032, Shanghai, China;Shanghai Xuhui Central Hospital, 200031, Shanghai, China;

关键词: CHD1L;    HIF-2α;    SIRT7;    Epigenetic reprogramming;    Sunitinib;   

DOI  :  10.1186/s13578-023-01113-4

 received in 2023-03-26, accepted in 2023-08-24,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundAberrant interplay between epigenetic reprogramming and hypoxia signaling contributes to renal cell carcinoma progression and drug resistance, which is an essential hallmark. How the chromatin remodelers enhance RCC malignancy remains to be poorly understood. We aimed to elucidate the roles of CHD1L in determining hypoxia signaling activation and sunitinib resistance.MethodsThe qRT-PCR, western blotting, and immunohistochemistry technologies were used to detect CHD1L expressions. Lentivirus transfection was used to generate stable CHD1L-KD cells. The roles of SIRT7/CHD1L were evaluated by CCK-8, wound healing, transwell assays, xenograft models, and tail-vein metastasis models. Co-immunoprecipitation, Chromatin Immunoprecipitation (ChIP), and luciferase reporter assays were conducted to explore epigenetic regulations.ResultsWe screened and validated that CHD1L is up-regulated in RCC and correlates with poorer prognosis of patients. CHD1L overexpression notably enhances cell proliferation, migration, and self-renewal capacities in vitro and in vivo. Mechanistically, SIRT7 physically interacts with CHDL1 and mediates the deacetylation of CHD1L. Wild-type SIRT7, but not H187Y dead mutant, stabilizes CHD1L protein levels via attenuating its ubiquitination levels. SIRT7 is increased in RCC and correlates with hazardous RCC clinical characteristics. SIRT7 depends on CHD1L to exert its tumor-promoting functions. Accumulated CHD1L amplifies HIF-2α-driven transcriptional programs via interacting with HIF-2α. CHD1L recruits BRD4 and increases the RNA polymerase II S2P loading. CHD1L ablation notably abolishes HIF-2α binding and subsequent transcriptional activation. CHD1L overexpression mediates the sunitinib resistance via sustaining VEGFA and targeting CHD1L reverses this effect. Specific CHD1L inhibitor (CHD1Li) shows a synergistic effect with sunitinib and strengthens its pharmaceutical effect.ConclusionsThese results uncover a CHD1L-mediated epigenetic mechanism of HIF-2α activation and downstream sunitinib resistance. The SIRT7–CHD1L–HIF-2α axis is highlighted to predict RCC prognosis and endows potential targets.

【 授权许可】

CC BY   
© Society of Chinese Bioscientists in America (SCBA) 2023

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