众多研究表明组蛋白甲基转移酶广泛参与肿瘤的发生发展及耐药过程中，并具备成为新预后标记物及治疗靶点的潜力。我们前期报道SMYD2在肾癌中发挥促癌作用，与患者预后密切相关，并影响肾癌对舒尼替尼的敏感性。后续研究发现CDKN2BAS1可以受SMYD2调控，上调原癌基因MMP2和RET的表达，促进肾癌对舒尼替尼的耐药。结合生物信息学分析及后续研究结果，我们提出科学假说：SMYD2可能通过与CDKN2BAS1启动子区域结合，使该区域H3K4me1水平升高，激活其转录，从而竞争性结合miR-2278，上调MMP2和RET的表达，调控肾透明细胞癌对舒尼替尼的耐药性。本项目拟通过研究SMYD2及CDKN2BAS1在肾癌耐药中的功能及作用机制，利用临床标本及患者肿瘤类器官模型验证，探究CDKN2BAS1和SMYD2作为预测药物敏感性的标志物及治疗耐药性肾癌新靶点的可能性，为肾癌精准治疗及药物研发提供新思路。

Many studies have shown that histone methyltransferases are widely involved in the process of tumorigenesis and drug resistance, and have the potential to become the new tumor prognostic molecular markers and therapeutic targets. We previously reported that the histone methyltransferase SMYD2 is closely related to renal cancer progression and patient prognosis. It plays a role as a tumor promoter and affect the sunitinib resistance in RCC. Subsequent research found that CDKN2BAS1 can be regulated by SMYD2, up-regulate the expression of the proto-oncogenes MMP2 and RET, and promote drug resistance to sunitinib. Based on the results of bioinformatic analysis and experiments, we speculate that SMYD2 may activate the expression of CDKN2BAS1 by binding to the promoter region and increase the level of H3K4me1 in the region, and CDKN2BAS1 promoted sunitinib resistance via competitively binding miR-2278 to promote MMP2 and RET expression in ccRCC cells. This project intends to study the function and mechanism of SMYD2 and CDKN2BAS1 in sunitinib resistant ccRCC cells, and explore the possibility of CDKN2BAS1 and SMYD2 as predictors of drug resistance and potential therapeutic targets for the clinical treatment of renal cancer via in vitro and vivo models, clinical samples and patient derived organoids, and provide new ideas for precise treatment and drug development of RCC.