Linear ubiquitination of PTEN impairs its function to promote prostate cancer progression
Linear ubiquitination of PTEN impairs its function to promote prostate cancer progression
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PTEN 的线性泛素化损害其促进前列腺癌进展的功能
DOI：
10.1038/s41388-022-02485-6
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发表时间：
2022-10-03
期刊：
影响因子：
8
通讯作者：
Yu, Jianxiu
中科院分区：
文献类型：
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作者：
Guo, Yanmin;He, Jianfeng;Yu, Jianxiu
PTEN在人类癌症中经常发生突变，导致PI3K/AKT信号过度激活，从而促进肿瘤发生和耐药。Met(1)-linked泛素化（M1-Ubi）也参与了癌症的进展，但其机制尚不明确。本研究发现，线性泛素链组装复合物（LUBAC）的重要组成部分HOIP通过pten依赖的方式增强AKT信号传导，从而促进前列腺癌（PCa）的进展。从机制上讲，M1-Ubi在K144和K197两个位点修饰PTEN，显著抑制PTEN磷酸酶活性，从而加速PCa的进展。更重要的是，我们发现高频突变体PTENR173H和PTENR173C在PCa患者中表现出M1-Ubi水平的增强，这损害了PTEN抑制AKT磷酸化和细胞生长的功能。我们还发现HOIP耗竭使PCa细胞对治疗药物BKM120和恩杂鲁胺敏感。此外，临床数据分析证实，在PCa患者标本中，HOIP上调并与AKT激活正相关，这可能促进PCa的进展，增加PCa生化复发的风险。总之，我们的研究揭示了PTEN M1-Ubi在调节AKT激活和PCa进展中的关键作用，这可能为PCa治疗提供新的策略。
PTEN is frequently mutated in human cancers, which leads to the excessive activation of PI3K/AKT signaling and thus promotes tumorigenesis and drug resistance. Met(1)-linked ubiquitination (M1-Ubi) is also involved in cancer progression, but the mechanism is poorly defined. Here we find that HOIP, one important component of linear ubiquitin chain assembly complex (LUBAC), promotes prostate cancer (PCa) progression by enhancing AKT signaling in a PTEN-dependent manner. Mechanistically, PTEN is modified by M1-Ubi at two sites K144 and K197, which significantly inhibits PTEN phosphatase activity and thus accelerates PCa progression. More importantly, we identify that the high-frequency mutants PTENR173H and PTENR173C in PCa patients showed the enhanced level of M1-Ubi, which impairs PTEN function in inhibition of AKT phosphorylation and cell growth. We also find that HOIP depletion sensitizes PCa cells to therapeutic agents BKM120 and Enzalutamide. Furthermore, the clinical data analyses confirm that HOIP is upregulated and positively correlated with AKT activation in PCa patient specimen, which may promote PCa progression and increase the risk of PCa biochemical relapse. Together, our study reveals a key role of PTEN M1-Ubi in regulation of AKT activation and PCa progression, which may propose a new strategy for PCa therapy.