Zhao Zitong, Xu Heyang, Wei Yuan, Sun Li, Song Yongmei
State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Departments of Gynecological Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital l & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China.
Biochim Biophys Acta Mol Basis Dis. 2023 Feb;1869(2):166594. doi: 10.1016/j.bbadis.2022.166594. Epub 2022 Nov 1.
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 vivo assays 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.
自噬是一种关键的细胞过程，存在于许多肿瘤中，并在肿瘤的促进和抑制中发挥双重作用。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关键作用。在此，我们探索了导致卵巢癌异常自噬的DUBs。TCGA数据分析表明，卵巢癌中自噬水平受到抑制，选择性自噬受体SQSTM1/p62异常高表达。我们筛选并鉴定出去泛素化酶PSMD14负向调节自噬水平。功能研究表明，PSMD14表达增加显著增强卵巢癌细胞的恶性程度，而敲低PSMD14则产生相反的效果。此外，体内实验表明，敲低PSMD14可抑制卵巢癌的生长、肺转移和腹腔转移。机制上，PSMD14直接与LRPPRC相互作用并抑制其泛素化，从而通过LRPPRC/Beclin1-Bcl-2/SQSTM1信号通路抑制自噬。接下来，我们证明PSMD14在卵巢癌中上调，且PSMD14的高表达与LRPPRC呈正相关。综上所述，我们阐明了自噬在调节卵巢癌表型中的作用，并深入了解了卵巢癌中自噬的调节机制。
