抑癌基因BAP1调控铁死亡及其抑制肿瘤的分子机制研究

抑癌基因BAP1在肾透明细胞癌等多种肿瘤中高发突变。我们前期研究首次发现，BAP1可以通过促进铁死亡发挥其抑癌功能。但BAP1调控靶基因表达、促进铁死亡和抑癌的分子机制及其在肿瘤治疗中的应用仍不清楚。为锁定介导BAP1功能的关键作用分子，我们通过质谱鉴定与BAP1相互作用的蛋白，结合生物化学、分子生物学、细胞生物学、肿瘤生物信息学分析等学科实验手段，阐明该蛋白参与BAP1调控靶基因表达、铁死亡和抑制肿瘤的作用机制。同时利用ChIP-Seq、ATAC-Seq等基因组学研究手段，深入剖析BAP1及其相互作用蛋白通过H2ub表观遗传调控基因表达的模式。针对BAP1突变肾癌细胞抵抗铁死亡的机理，研究抗肿瘤药物索拉菲尼联用铁死亡诱导剂的用药策略并验证其疗效，加速BAP1基因突变肿瘤患者的个体化医疗进程。

Tumor suppressor gene BAP1 is frequently mutated in multiple types of tumor including kidney renal clear cell carcinoma. Our previous research demonstrated that BAP1 reduced epigenetic modification of monoubiquitylation on H2A in tumor cells, inhibited cystine transporter protein SLC7A11 expression, regulated ferroptosis and suppressed tumor. But the molecular mechanism by which BAP1 controls target gene expression, ferroptosis and tumor suppression, as well as its applications in cancer treatment remain further investigation. To explore key molecule mediating the gene regulation and cellular functions controlled by BAP1, we seek to identify BAP1-associated proteins through tandem mass spectrometry. Combining experimental tools involved in biochemistry, molecular biology, cellular biology and tumor bioinformatics, verify the important role of BAP1-associated protein in regulating its functions in controlling gene expression, ferroptosis and tumor suppression. Meanwhile, deeply explore the modulating model by BAP1 and its associated protein in a H2Aub-dependent manner through genome-wide analyses such as ChIP-Seq and ATAC-Seq. Based on the important role of BAP1 in promoting ferroptosis and suppressing tumor, develop therapeutic strategy via combining anti-cancer drug sorafenib and ferroptosis-inducing reagents, and validate treatment efficacy in kidney tumors with BAP1 gene mutations, which will substantially accelerate the utilization of personal medicine in BAP1-mutated cancer patients.