Deubiquitylase PSMD14 inhibits autophagy to promote ovarian cancer progression via stabilization of LRPPRC
Deubiquitylase PSMD14 inhibits autophagy to promote ovarian cancer progression via stabilization of LRPPRC
复制标题
去泛素化酶 PSMD14 通过稳定 LRPPRC 抑制自噬促进卵巢癌进展
DOI：
10.1016/j.bbadis.2022.166594
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Yongmei Song
中科院分区：
文献类型：
--
作者：
Zitong Zhao;Heyang Xu;Yuan Wei;Li Sun;Yongmei Song
自噬是一种重要的细胞过程，存在于多种肿瘤中，在肿瘤的发生发展中起着促癌和抑癌的双重作用。然而，异常自噬在卵巢癌中的作用和机制仍不清楚。泛素-蛋白酶体途径是特异性蛋白质降解的最重要途径。去泛素化酶（DUBs）在肿瘤发生和发展的所有阶段都起着至关重要的作用。在此，我们探讨了DUBs在卵巢癌中导致异常自噬。TCGA数据分析显示，自噬水平受到抑制，选择性自噬受体SQSTM 1/p62在卵巢癌中异常高表达。我们筛选并鉴定了去泛素化酶PSMD 14负调控自噬水平。功能研究表明，PSMD 14表达增加显著增强卵巢癌细胞的恶性度，而PSMD 14的敲低具有相反的效果。此外，体内试验表明，PSMD 14的敲除可以抑制卵巢癌的生长、肺和腹部转移。在机制上，PSMD 14直接与LRPPRC相互作用并抑制其泛素化，从而通过LRPPRC/Beclin 1-Bcl-2/SQSTM 1信号通路抑制自噬。接下来，我们证明了PSMD 14在卵巢癌中上调，并且PSMD 14的高表达与LRPPRC正相关。总之，我们阐明了自噬在调节卵巢癌表型中的作用，并为卵巢癌中自噬的调节机制提供了新的见解。
Autophagy is a key cellular process, which exists in many tumors and plays dual roles in tumor promotion and suppression. However, the role and mechanism of aberrant autophagy in ovarian cancer remains unclear. Ubiquitin-proteasome pathway is the most important pathway for specific protein degradation. Deubiquitinases (DUBs) have crucial roles in all the stages of tumorigenesis and progression. Herein, we explore the DUBs which contribute to aberrant autophagy in ovarian cancer. TCGA data analysis shows that the autophagy level is suppressed, and the selective autophagy receptor SQSTM1/p62 is abnormally high expressed in ovarian cancer. We screen and identify that the deubiquitinase PSMD14 negatively regulates autophagy level. Functional studies show that increased PSMD14 expression remarkably enhances ovarian cancer cells malignancy, whereas knockdown of PSMD14 has the opposite effect. Furthermore,in vivoassays show that knockdown of PSMD14 inhibits the growth, lung and abdominal metastasis of ovarian cancer. Mechanistically, PSMD14 directly interacts with LRPPRC and inhibits its ubiquitination, thereby inhibiting autophagy through LRPPRC/Beclin1-Bcl-2/SQSTM1 signaling pathway. Next, we demonstrate that PSMD14 is upregulated in ovarian cancer and high expression of PSMD14 positively correlates with LRPPRC. Taken together, we clarify the role of autophagy in regulating the ovarian cancer phenotype and provide insights into regulatory mechanism of autophagy in ovarian cancer.