HIF2α半胱氨酸棕榈酰化修饰促进透明细胞肾癌恶性进展的分子机制研究

透明细胞肾细胞癌(ccRCC)起源于肾小管上皮细胞，具有脂类代谢产物累积的特征，约90% ccRCC丢失抑癌基因VHL，导致HIF1/2α激活，然而脂类代谢产物累积与HIF1/2α激活两者之间是否存在着调控关系仍然未知。申请人前期研究结果显示HIF2α携带了棕榈酰化修饰，棕榈酰化显著增强HIF2α转录活性，并鉴定出ZDHHC23是HIF2α的棕榈酰化转移酶，进一步分子机制探索发现ZDHHC23是HIF2α的靶基因，提示ZDHHC23与HIF2α形成一个正反馈环路增强HIF2α的转录活性。敲低ZDHHC23可有效消除高脂饮食对移植瘤生长的促进作用，提示ZDHHC23介导的HIF2α棕榈酰化促进ccRCC恶性进展。申请人将进一步通过体外生化实验、培养细胞模型以及体内小鼠模型研究HIF2α棕榈酰化在ccRCC发生、进展过程中扮演的角色。本研究有望通过揭示代谢弱点，为临床治疗ccRCC提供新靶点。

Clear cell renal cell carcinoma (ccRCC) is a malignant kidney cancer derived from renal tubular epithelial cells and characterized with lipid accumulation in cytosol. Hypoxia-inducible factors (HIF) 1/2α were activated due to pVHL loss in 90% of ccRCC approximately, however, the intrinsic relationship between lipid accumulation and HIF 1/2α activation is still enigmatic. Our preliminary data showed that HIF 2α, but not HIF 1α, was S-palmitoylated and S-palmitoylation dramatically activated transcription activity of HIF 2α and we identified ZDHHC23 as a palmitoyl acyltransferase that regulates HIF 2α S-palmitoylation. Mechanistically, our evidences supported that ZDHHC23 is a target gene of HIF 2α, ZDHHC23 and HIF2α formed a positive-feedback loop to enhance the transcriptional activity of HIF2α. In addition, ZDHHC23 knockdown abolished the effect of high-fat diet promoted-tumor growth in ccRCC xenograft mouse model, which implied that ZDHHC23-mediated HIF 2α S-palmitoylation promotes the malignant progression of ccRCC. We would further decipher the roles of HIF 2α S-palmitoylation in initiation and development of ccRCC through the integrated approaches of biochemical assays and culture cell model in vitro, as well as mouse model in vivo. Metabolic vulnerability uncovered in this study may provide a molecular basis for developing new therapeutic interventions for ccRCC.