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Gan, Wenjian

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Gan

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Wenjian

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Gan, Wenjian

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2013 - 20173

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Author's Publications: search.filters.isAuthorOfPublication.9a7a34d4-864d-4061-8699-1ebfa0488267

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Now showing 1 - 3 of 3
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    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, Wenyi
    The 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.
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    Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signaling to suppress tumorigenesis
    (2013) Liu, Pengda; Gan, Wenjian; Inuzuka, Hiroyuki; Lazorchak, Adam S; Gao, Daming; Arojo, Omotooke; Liu, Dou; Wan, Lixin; Zhai, Bo; Yu, Yonghao; Yuan, Min; Kim, Byeong Mo; Shaik, Shavali; Menon, Suchithra; Gygi, Steven; Lee, Tae Ho; Asara, John; Manning, Brendan; Blenis, John; Su, Bing; Wei, Wenyi
    The mechanistic target of rapamycin (mTOR) functions as a critical regulator of cellular growth and metabolism by forming multi-component, yet functionally distinct complexes mTORC1 and mTORC2. Although mTORC2 has been implicated in mTORC1 activation, little is known about how mTORC2 is regulated. Here we report that phosphorylation of Sin1 at T86 and T398 suppresses mTORC2 kinase activity by dissociating Sin1 from mTORC2. Importantly, Sin1 phosphorylation, triggered by S6K or Akt, in a cellular context-dependent manner, inhibits not only insulin/IGF-1-mediated, but also PDGF or EGF-induced Akt phosphorylation by mTORC2, demonstrating a negative regulation of mTORC2 independent of IRS-1 and Grb10. Lastly, a cancer patient-derived Sin1-R81T mutation impairs Sin1 phosphorylation, leading to hyper-mTORC2 activation via bypassing this negative regulation. Together, our work reveals a Sin1 phosphorylation-dependent mTORC2 regulation, providing a potential molecular mechanism by which mutations in the mTORC1/S6K/Sin1 signaling axis might cause aberrant hyper-activation of mTORC2/Akt that facilitates tumorigenesis.
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    Dual phosphorylation of Sin1 at T86 and T398 negatively regulates mTORC2 complex integrity and activity
    (Higher Education Press, 2014) Liu, Pengda; Guo, Jianping; Gan, Wenjian; Wei, Wenyi
    Mammalian target of rapamycin (mTOR) plays essential roles in cell proliferation, survival and metabolism by forming at least two functional distinct multi-protein complexes, mTORC1 and mTORC2. External growth signals can be received and interpreted by mTORC2 and further transduced to mTORC1. On the other hand, mTORC1 can sense inner-cellular physiological cues such as amino acids and energy states and can indirectly suppress mTORC2 activity in part through phosphorylation of its upstream adaptors, IRS-1 or Grb10, under insulin or IGF-1 stimulation conditions. To date, upstream signaling pathways governing mTORC1 activation have been studied extensively, while the mechanisms modulating mTORC2 activity remain largely elusive. We recently reported that Sin1, an essential mTORC2 subunit, was phosphorylated by either Akt or S6K in a cellular context-dependent manner. More importantly, phosphorylation of Sin1 at T86 and T398 led to a dissociation of Sin1 from the functional mTORC2 holo-enzyme, resulting in reduced Akt activity and sensitizing cells to various apoptotic challenges. Notably, an ovarian cancer patient-derived Sin1-R81T mutation abolished Sin1-T86 phosphorylation by disrupting the canonical S6K-phoshorylation motif, thereby bypassing Sin1-phosphorylation-mediated suppression of mTORC2 and leading to sustained Akt signaling to promote tumorigenesis. Our work therefore provided physiological and pathological evidence to reveal the biological significance of Sin1 phosphorylation-mediated suppression of the mTOR/Akt oncogenic signaling, and further suggested that misregulation of this process might contribute to Akt hyper-activation that is frequently observed in human cancers.