• 方向一：肿瘤发生发展过程中重要蛋白质的泛素化修饰调控机制研究

阐明了多个蛋白质泛素化修饰调控异常与恶性肿瘤如前列腺癌、卵巢癌、子宫内膜癌等的关系：1）SPOP介导BET家族蛋白的泛素化降解，前列腺癌中SPOP突变导致BET蛋白积累，激活AKT-mTORC1信号通路，产生BET抑制剂天然耐药现象。2) CRL2-KLHDC3 E3泛素连接酶复合体促进p14ARF泛素化降解，抑制细胞的铁死亡，KLHDC3异常扩增通过p14ARF-NRF2-SLC7A11通路促进卵巢癌的生长。3）RNF12泛素化降解MDM2，上调p53蛋白，激活p53信号通路，从而抑制肿瘤。4）SPOP泛素化降解组蛋白甲基转移酶GLP，SPOP突变稳定GLP/G9a，诱导细胞整体DNA超甲基化。5)SPOP突变导致雌激素受体ERα异常积累,促进肿瘤； SPOP促进孕激素受体PR的泛素化降解； SPOP促进内质网压力调控因子DDIT3的泛素降解。6）Itch介导肿瘤抑制蛋白TXNIP的泛素化降解，调控细胞内ROS水平。

发表论文：

• Zhang P#, Wang D#, Zhao Y#, Ren S#, Gao K#, Ye Z, Wang S, Pan CW, Zhu Y, Yan Y, Yang Y, Wu D, He Y, Zhang J, Lu D, Liu X, Yu L, Zhao S, Li Y, Lin D, Wang Y, Wang L, Chen Y, Sun Y, Wang C, Huang H. Intrinsic BET inhibitor resistance in SPOP-mutated prostate cancer is mediated by BET protein stabilization and AKT-mTORC1 activation. Nat Med. 2017 Sep;23(9):1055-1062.

• Zhang P#*, Gao K#*, Zhang L#, Sun H, Zhao X, Liu Y, Lv Z, Shi Q, Chen Y, Jiao D, Li Y, Gu W*, Wang C*. CRL2-KLHDC3 E3 ubiquitin ligase complex suppresses ferroptosis through promoting p14(ARF) degradation. Cell Death Differ. 2021 Nov 6.

• Gao K, Wang C, Jin X, Xiao J, Zhang E, Yang X, Wang D, Huang H, Yu L*, Zhang P*. RNF12 promotes p53-dependent cell growth suppression and apoptosis by targeting MDM2 for destruction. Cancer Lett. 2016 May 28;375(1):133-141.

• Zhang J#, Gao K#, Xie H#, Wang D#, Zhang P#, Wei T, Yan Y, Pan Y, Ye W, Chen H, Shi Q, Li Y, Zhao SM, Hou X, Weroha SJ, Wang Y, Zhang J, Karnes RJ, He HH, Wang L, Wang C, Huang H.SPOP mutation induces DNA methylation via stabilizing GLP/G9a.Nat Commun. 2021 Sep 29;12(1):5716.

• Wang Q#, Zhang P#, Zhang W, Zhang X, Chen J, Ding P, Li L, Lv X, Li L, Hu W. PI3K Activation Is Enhanced by FOXM1D Binding to p110 and p85 Subunits. Signal Transduct Target Ther. 2020 Jun 30;5(1):105.

• Gao K, Zhang Y, Shi Q, Zhang J, Zhang L, Sun H, Jiao D, Zhao X, Tao H, Wei Y, Wang Y, Saiyin H, Zhao SM, Li Y, Zhang P*, Wang C*. iASPP-PP1 complex is required for cytokinetic abscission by controlling CEP55 dephosphorylation. Cell Death Dis. 2018 May 1;9(5):528.

• Zhang P#, Gao K#, Jin X, Ma J, Peng J, Wumaier R, Tang Y, Zhang Y, An J, Yan Q, Dong Y, Huang H, Yu L, Wang C. Endometrial cancer-associated mutants of SPOP are defective in regulating estrogen receptor-α protein turnover. Cell Death Dis. 2015 Mar 12;6:e1687.

• Zhang P#, Gao K#, Tang Y, Jin X, An J, Yu H, Wang H, Zhang Y, Wang D, Huang H, Yu L, Wang C. Destruction of DDIT3/CHOP Protein by Wild-Type SPOP but Not Prostate Cancer-Associated Mutants. Hum Mutat. 2014 Sep;35(9):1142-51.

• Gao K, Jin X, Tang Y, Ma J, Peng J, Yu L, Zhang P*, Wang C*  Tumor suppressor SPOP mediates the proteasomal degradation of progesterone receptors (PRs) in breast cancer cells. American Journal of Cancer Research. 2015 Sep 15;5(10):3210-20

• Zhang P#, Wang C#, Gao K, Wang D, Mao J, An J, Xu C, Wu D, Yu H, Liu JO, Yu L. The ubiquitin ligase itch regulates apoptosis by targeting thioredoxin-interacting protein for ubiquitin-dependent degradation. J Biol Chem. 2010 Mar 19;285(12):8869-79.