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Deubiquitinase UCHL1 Maintains Protein Homeostasis through the PSMA7-APEH-Proteasome Axis in High-grade Serous Ovarian Carcinoma.
- Source :
-
Molecular cancer research : MCR [Mol Cancer Res] 2021 Jul; Vol. 19 (7), pp. 1168-1181. Date of Electronic Publication: 2021 Mar 22. - Publication Year :
- 2021
-
Abstract
- High-grade serous ovarian cancer (HGSOC) is characterized by chromosomal instability, DNA damage, oxidative stress, and high metabolic demand that exacerbate misfolded, unfolded, and damaged protein burden resulting in increased proteotoxicity. However, the underlying mechanisms that maintain protein homeostasis to promote HGSOC growth remain poorly understood. This study reports that the neuronal deubiquitinating enzyme, ubiquitin carboxyl-terminal hydrolase L1 (UCHL1), is overexpressed in HGSOC and maintains protein homeostasis. UCHL1 expression was markedly increased in HGSOC patient tumors and serous tubal intraepithelial carcinoma (HGSOC precursor lesions). High UCHL1 levels correlated with higher tumor grade and poor patient survival. UCHL1 inhibition reduced HGSOC cell proliferation and invasion, as well as significantly decreased the in vivo metastatic growth of ovarian cancer xenografts. Transcriptional profiling of UCHL1-silenced HGSOC cells revealed downregulation of genes implicated with proteasome activity along with upregulation of endoplasmic reticulum stress-induced genes. Reduced expression of proteasome subunit alpha 7 (PSMA7) and acylaminoacyl peptide hydrolase (APEH), upon silencing of UCHL1, resulted in a significant decrease in proteasome activity, impaired protein degradation, and abrogated HGSOC growth. Furthermore, the accumulation of polyubiquitinated proteins in the UCHL1-silenced cells led to attenuation of mTORC1 activity and protein synthesis, and induction of terminal unfolded protein response. Collectively, these results indicate that UCHL1 promotes HGSOC growth by mediating protein homeostasis through the PSMA7-APEH-proteasome axis. IMPLICATIONS: This study identifies the novel links in the proteostasis network to target protein homeostasis in HGSOC and recognizes the potential of inhibiting UCHL1 and APEH to sensitize cancer cells to proteotoxic stress in solid tumors.<br /> (©2021 American Association for Cancer Research.)
- Subjects :
- Animals
Cell Line, Tumor
Cystadenocarcinoma, Serous drug therapy
Cystadenocarcinoma, Serous metabolism
Female
Gene Expression Profiling methods
Gene Expression Regulation, Neoplastic
Humans
Indoles pharmacology
Kaplan-Meier Estimate
Mice, Nude
Neoplasm Grading
Ovarian Neoplasms drug therapy
Ovarian Neoplasms metabolism
Oximes pharmacology
Peptide Hydrolases metabolism
Proteasome Endopeptidase Complex metabolism
Ubiquitin Thiolesterase antagonists & inhibitors
Ubiquitin Thiolesterase metabolism
Xenograft Model Antitumor Assays methods
Mice
Cystadenocarcinoma, Serous genetics
Ovarian Neoplasms genetics
Peptide Hydrolases genetics
Proteasome Endopeptidase Complex genetics
Proteostasis genetics
Ubiquitin Thiolesterase genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3125
- Volume :
- 19
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Molecular cancer research : MCR
- Publication Type :
- Academic Journal
- Accession number :
- 33753553
- Full Text :
- https://doi.org/10.1158/1541-7786.MCR-20-0883