Person: Guo, Jianping
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Guo
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Jianping
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Guo, Jianping
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Publication AKT methylation by SETDB1 promotes AKT kinase activity and oncogenic functions(Springer Science and Business Media LLC, 2019-01-28) Guo, Jianping; Dai, Xiangpeng; Laurent, Benoit; Zheng, Nana; Gan, Wenjian; Zhang, Jian; Guo, Ailan; Yuan, Min; Liu, Pengda; Asara, John M.; Toker, Alex; Shi, Yang; Pandolfi, Pier Paolo; Wei, WenyiAberrant activation of Akt disturbs proliferation, survival and metabolic homeostasis of various human cancers. Thus, it is critical to understand upstream signaling pathways governing Akt activation. Here, we report that Akt undergoes SETDB1-mediated lysine-methylation to promote its activation, which is antagonized by the Jumonji-family demethylase, KDM4B. Notably, compared with wild-type mice, mice harboring non-methylated mutant Akt1 not only exhibited reduced body size, but also were less prone to carcinogen-induced skin tumors in part due to reduced Akt activation. Mechanistically, Phosphatidylinositol (3,4,5)-trisphosphate (PIP3) interaction with Akt facilitates its interaction with SETDB1 for subsequent Akt methylation, which in turn sustains Akt phosphorylation. Pathologically, genetic alterations including SETDB1 amplification aberrantly promote Akt methylation to facilitate its activation and oncogenic functions. Thus, Akt methylation is an important step synergizing with PI3K signaling to control Akt activation, suggesting that targeting the SETDB1 signaling could be a potential therapeutic strategy for combatting hyperactive Akt-driven cancers.Publication Cullin 3SPOP ubiquitin E3 ligase promotes the poly-ubiquitination and degradation of HDAC6(Impact Journals LLC, 2017) Tan, Yuyong; Ci, Yanpeng; Dai, Xiangpeng; Wu, Fei; Guo, Jianping; Liu, Deliang; North, Brian; Huo, Jirong; Zhang, JinfangThe histone deacetylase 6 (HDAC6) plays critical roles in human tumorigenesis and metastasis. As such, HDAC6-selective inhibitors have entered clinical trials for cancer therapy. However, the upstream regulator(s), especially ubiquitin E3 ligase(s), responsible for controlling the protein stability of HDAC6 remains largely undefined. Here, we report that Cullin 3SPOP earmarks HDAC6 for poly-ubiquitination and degradation. We found that the proteasome inhibitor MG132, or the Cullin-based E3 ligases inhibitor MLN4924, but not the autophagosome-lysosome inhibitor bafilomycin A1, stabilized endogenous HDAC6 protein in multiple cancer cell lines. Furthermore, we demonstrated that Cullin 3-based ubiquitin E3 ligase(s) primarily reduced the stability of HDAC6. Importantly, we identified SPOP, an adaptor protein of Cullin 3 family E3 ligases, specifically interacted with HDAC6, and promoted its poly-ubiquitination and subsequent degradation in cells. Notably, cancer-derived SPOP mutants disrupted their binding with HDAC6 and thereby failed to promote HDAC6 degradation. More importantly, increased cellular proliferation and migration in SPOP-depleted HCT116 colon cancer cells could be partly reversed by additional depletion of HDAC6, suggesting that HDAC6 is a key downstream effector for SPOP tumor suppressor function. Together, our data identify the tumor suppressor SPOP as an upstream negative regulator for HDAC6 stability, and SPOP loss-of-function mutations might lead to elevated levels of the HDAC6 oncoprotein to facilitate tumorigenesis and metastasis in various human cancers.Publication Prostate cancer-associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4(2017) Dai, Xiangpeng; Gan, Wenjian; Li, Xiaoning; Wang, Shangqian; Zhang, Wei; Huang, Ling; Liu, Shengwu; Zhong, Qing; Guo, Jianping; Zhang, Jinfang; Chen, Ting; Shimizu, Kouhei; Beca, Francisco; Blattner, Mirjam; Vasudevan, Divya; Buckley, Dennis L.; Qi, Jun; Buser, Lorenz; Liu, Pengda; Inuzuka, Hiroyuki; Beck, Andrew; Wang, Liewei; Wild, Peter J.; Garraway, Levi; Rubin, Mark A.; Barbieri, Christopher E.; Wong, Kwok-Kin; Muthuswamy, Senthil; Huang, Jiaoti; Chen, Yu; Bradner, James E; Wei, WenyiThe bromodomain and extra-terminal (BET) family of proteins, comprised of four members including BRD2, BRD3, BRD4 and the testis-specific isoform BRDT, largely function as transcriptional co-activators 1–3 and play critical roles in various cellular processes, including cell cycle, apoptosis, migration and invasion 4,5. As such, BET proteins enhance the oncogenic functions of major cancer drivers by either elevating their expression such as c-Myc in leukemia 6,7 or by promoting transcriptional activities of oncogenic factors such as AR and ERG in the prostate cancer setting 8. Pathologically, BET proteins are frequently overexpressed and clinically linked to various types of human cancers 5,9,10, therefore pursued as attractive therapeutic targets for selective inhibition in patients. To this end, a number of bromodomain inhibitors, including JQ1 and I-BET, have been developed 11,12 and shown promising outcomes in early clinical trials. Despite resistance to BET inhibitor has been documented in pre-clinical models 13–15 the molecular mechanisms underlying acquired resistance are largely unknown. Here, we report that Cullin 3SPOP earmarks BET proteins including BRD2, BRD3 and BRD4 for ubiquitination-mediated degradation. Pathologically, prostate cancer-associated SPOP mutants fail to interact with and promote the destruction of BET proteins, leading to their elevated abundance in SPOP-deficient prostate cancer. As a result, prostate cancer cells and prostate cancer patient-derived organoids harboring SPOP mutations are more resistant to BET inhibitor-induced cell growth arrest and apoptosis. Therefore, our results elucidate the tumor suppressor role of SPOP in prostate cancer by negatively controlling BET protein stability, and also provide a molecular mechanism for BET inhibitor resistance in prostate cancer patients bearing SPOP mutations.Publication Cyclin D-CDK4 kinase destabilizes PD-L1 via Cul3SPOP to control cancer immune surveillance(2017) Zhang, Jinfang; Bu, Xia; Wang, Haizhen; Zhu, Yasheng; Geng, Yan; Nihira, Naoe; Tan, Yuyong; Ci, Yanpeng; Wu, Fei; Dai, Xiangpeng; Guo, Jianping; Huang, Yu-Han; Fan, Caoqi; Ren, Shancheng; Sun, Yinghao; Freeman, Gordon; Sicinski, Piotr; Wei, WenyiPublication Angina and Future Cardiovascular Events in Stable Patients With Coronary Artery Disease: Insights From the Reduction of Atherothrombosis for Continued Health (REACH) Registry(John Wiley and Sons Inc., 2016) Eisen, Alon; Bhatt, Deepak; Steg, P. Gabriel; Eagle, Kim A.; Goto, Shinya; Guo, Jianping; Smith, Sidney C.; Ohman, E. Magnus; Scirica, BenjaminBackground: The extent to which angina is associated with future cardiovascular events in patients with coronary artery disease has long been debated. Methods and Results: Included were outpatients with established coronary artery disease who were enrolled in the REACH registry and were followed for 4 years. Angina at baseline was defined as necessitating episodic or permanent antianginal treatment. The primary end point was the composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included heart failure, cardiovascular hospitalizations, and coronary revascularization. The independent association between angina and first/total events was examined using Cox and logistic regression models. Out of 26 159 patients with established coronary artery disease, 13 619 (52%) had angina at baseline. Compared with patients without angina, patients with angina were more likely to be older, female, and had more heart failure and polyvascular disease (P<0.001 for each). Compared with patients without angina, patients with angina had higher rates of first primary end‐point event (14.2% versus 16.3%, unadjusted hazard ratio 1.19, CI 1.11–1.27, P<0.001; adjusted hazard ratio 1.06, CI 0.99–1.14, P=0.11), and total primary end‐point events (adjusted risk ratio 1.08, CI 1.01–1.16, P=0.03). Patients with angina were at increased risk for heart failure (adjusted odds ratio 1.17, CI 1.06–1.28, P=0.002), cardiovascular hospitalizations (adjusted odds ratio 1.29, CI 1.21–1.38, P<0.001), and coronary revascularization (adjusted odds ratio 1.23, CI 1.13–1.34, P<0.001). Conclusions: Patients with stable coronary artery disease and angina have higher rates of future cardiovascular events compared with patients without angina. After adjustment, angina was only weakly associated with cardiovascular death, myocardial infarction, or stroke, but significantly associated with heart failure, cardiovascular hospitalization, and coronary revascularization.