SPOP是一个Cullin3家族泛素E3连接酶的底物识别亚基，近年来高通量测序发现其在子宫内膜癌和前列腺癌中存在高频失活突变，但致癌机制尚未得到阐明。申请人就此展开研究，陆续发现SPOP可以通过降解各种底物如BET（Nat Med，2017）、ERα（Cell Death Dis，2015）和DDIT3（Hum Mutat，2014）等参与肿瘤的发生发展。前期工作中我们筛选发现转录因子IRF1是SPOP的互作蛋白。SPOP可以通过降解IRF1抑制免疫调节分子PD-L1的表达，而子宫内膜癌来源的SPOP突变体则丧失了与IRF1结合并泛素化降解的能力。本研究将从分子、细胞、模式动物和肿瘤样本等多个层次，系统阐明子宫内膜癌SPOP突变导致IRF1蛋白异常积累，进而促进PD-L1转录及其介导的肿瘤细胞免疫逃逸的新机制，为PD1/PD-L1抑制剂在子宫内膜癌精准治疗中的应用提供重要的理论依据。

Characterization of the exome and genome of cancers by next-generation sequencing has identified numerous genetic alternations. SPOP was identified as one of the most frequently affected genes by somatic point mutations in endometrial cancer and prostate cancer. However, how SPOP mutations contribute to endometrial tumorigenesis or prostate tumorigenesis remains to be elucidated. We are interested in the underlying mechanism and revealed that SPOP is involved in tumorigenesis and cancer progression by degrading several substrates, such as BET (Nat Med，2017), ERα (Cell Death Dis，2015) and DDIT3 (Hum Mutat，2014). In this proposal, we identified transcriptional factor IRF1 as a novel SPOP interactor. SPOP represses PD-L1 transcription by targeting IRF for ubiquitin-dependent degradation. Strikingly, endometrial cancer-associated mutants of SPOP are defective in IRF1 binding and promoting IRF1 degradation. This study revealed novel molecular events underlying the regulation of IRF1/PD-L1 axis, and provided insights in understanding the relationship between SPOP mutations and immunoescape in endometrial cancer.