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论文题目: AKT-mediated stabilization of histone methyltransferase WHSC1 promotes prostate cancer metastasis
英文论文题目: AKT-mediated stabilization of histone methyltransferase WHSC1 promotes prostate cancer metastasis
第一作者: Li, N; Xue, W; Yuan, HR; Dong, BJ; Ding, YF; Liu, YF; Jiang, M; Kan, S; Sun, TY; Ren, JL; Pan, Q; Li, X; Zhang, PY; Hu, GH; Wang, Y; Wang, XM; Li, QT; Qin, J
英文第一作者: Li, N; Xue, W; Yuan, HR; Dong, BJ; Ding, YF; Liu, YF; Jiang, M; Kan, S; Sun, TY; Ren, JL; Pan, Q; Li, X; Zhang, PY; Hu, GH; Wang, Y; Wang, XM; Li, QT; Qin, J
联系作者: Qin, J (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, Ctr Excellence Mol Cell Sci, Key Lab Stem Cell Biol,Inst Hlth Sci, 320 Yue Yang Rd, Shanghai 200031, Peoples R China.
英文联系作者: Qin, J (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, Ctr Excellence Mol Cell Sci, Key Lab Stem Cell Biol,Inst Hlth Sci, 320 Yue Yang Rd, Shanghai 200031, Peoples R China.
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发表年度: 2017
卷: 127
期: 4
页码: 1284-1302
摘要: Loss of phosphatase and tensin homolog (PTEN) and activation of the PI3K/AKT signaling pathway are hallmarks of prostate cancer (PCa). However, these alterations alone are insufficient for cells to acquire metastatic traits. Here, we have shown that the histone dimethyl transferase WHSC1 critically drives indolent PTEN-null tumors to become metastatic PCa. In a PTEN-null murine PCa model, WHSC1 overexpression in prostate epithelium cooperated with Pten deletion to produce a metastasis-prone tumor. Conversely, genetic ablation of Whsc1 prevented tumor progression in PTEN-null mice. Molecular characterization revealed that increased AKT activity due to PTEN loss directly phosphorylates WHSC1 at S172, preventing WHSC1 degradation by CRL4(Cdt2) E3 ligase. Increased WHSC1 expression transcriptionally upregulates expression of RICTOR, a pivotal component of mTOR complex 2 (mTORC2), to further enhance AKT activity. Therefore, the AKT/WHSC1/mTORC2 signaling cascade represents a vicious feedback loop that elicits unrestrained AKT signaling. Furthermore, we determined that WHSC1 positively regulates Rac1 transcription to increase tumor cell motility. The biological importance of a WHSC1-mediated signaling cascade is substantiated by patient sample analysis in which WHSC1 signaling is tightly correlated with disease progression and recurrence. Taken together, our findings highlight a pivotal link between an epigenetic regulator, WHSC1, and key intracellular signaling molecules, AKT, RICTOR, and Rac1, to drive PCa metastasis.
英文摘要: Loss of phosphatase and tensin homolog (PTEN) and activation of the PI3K/AKT signaling pathway are hallmarks of prostate cancer (PCa). However, these alterations alone are insufficient for cells to acquire metastatic traits. Here, we have shown that the histone dimethyl transferase WHSC1 critically drives indolent PTEN-null tumors to become metastatic PCa. In a PTEN-null murine PCa model, WHSC1 overexpression in prostate epithelium cooperated with Pten deletion to produce a metastasis-prone tumor. Conversely, genetic ablation of Whsc1 prevented tumor progression in PTEN-null mice. Molecular characterization revealed that increased AKT activity due to PTEN loss directly phosphorylates WHSC1 at S172, preventing WHSC1 degradation by CRL4(Cdt2) E3 ligase. Increased WHSC1 expression transcriptionally upregulates expression of RICTOR, a pivotal component of mTOR complex 2 (mTORC2), to further enhance AKT activity. Therefore, the AKT/WHSC1/mTORC2 signaling cascade represents a vicious feedback loop that elicits unrestrained AKT signaling. Furthermore, we determined that WHSC1 positively regulates Rac1 transcription to increase tumor cell motility. The biological importance of a WHSC1-mediated signaling cascade is substantiated by patient sample analysis in which WHSC1 signaling is tightly correlated with disease progression and recurrence. Taken together, our findings highlight a pivotal link between an epigenetic regulator, WHSC1, and key intracellular signaling molecules, AKT, RICTOR, and Rac1, to drive PCa metastasis.
刊物名称: JOURNAL OF CLINICAL INVESTIGATION
英文刊物名称: JOURNAL OF CLINICAL INVESTIGATION
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学科: Medicine, Research & Experimental
英文学科: Medicine, Research & Experimental
影响因子: 12.784
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论文类别: Article
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