异常的表观遗传重编程与缺氧信号传导之间的相互作用，促进了肾细胞癌的进展和药物耐药性，这是一项重要的特征。染色质重塑因子如何增强RCC恶性程度仍然不明确。我们旨在阐明CHD1L在决定缺氧信号激活和索尼替尼耐药性中的作用。利用qRT-PCR、Western blot和免疫组织化学技术检测CHD1L表达。利用慢病毒转染产生稳定的CHD1L-KD细胞。通过CCK-8、划痕愈合、转移实验、移植瘤模型和尾静脉转移模型评估SIRT7/CHD1L的作用。通过共免疫沉淀、染色质免疫沉淀（ChIP）和荧光素酶报告基因实验探索表观遗传调控。我们筛选和验证了CHD1L在RCC中上调，并与患者预后较差相关。CHD1L的过表达显著增强了体外和体内细胞增殖、迁移和自我更新能力。机制上，SIRT7与CHDL1发生物理相互作用，并介导CHD1L的去乙酰化。野生型SIRT7能够稳定CHD1L蛋白水平，而H187Y突变型不能。SIRT7在RCC中增加并与危险性RCC临床特征相关。SIRT7依赖于CHD1L发挥其促癌功能。积累的CHD1L通过与HIF-2α相互作用增强了HIF-2α驱动的转录程序。CHD1L招募BRD4并增加RNA聚合酶II S2P的载荷。CHD1L消除明显地废除了HIF-2α的结合和随后的转录活化。CHD1L的过表达通过维持VEGFA介导索尼替尼耐药性，并靶向CHD1L可以逆转这种效应。特定的CHD1L抑制剂（CHD1Li）与索尼替尼显示协同效应，并增强其药效。以上结果揭示了一个CHD1L介导的HIF-2α激活的表观遗传机制以及下游索尼替尼耐药性。SIRT7-CHD1L-HIF-2α轴突出了预测RCC预后并具有潜在的靶点。© 2023年美国华人生物科学家协会（SCBA）。

Aberrant 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.The 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.We 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.These 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.© 2023. Society of Chinese Bioscientists in America (SCBA).