Deubiquitinase UCHL1 Maintains Protein Homeostasis through PSMA7-APEH-Proteasome Axis in High-Grade Serous Ovarian Carcinoma

High-grade serous ovarian cancer (HGSOC) is characterized by chromosomal instability, DNA damage, oxidative stress, and high metabolic demand, which 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. In this study, we report 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 through the outer layers of omentum as well as significantly decreased the in vivo metastatic tumor growth in ovarian cancer xenografts. Transcriptional profiling of UCHL1 silenced HGSOC cells revealed the down-regulation of genes implicated with proteasome activity along with the upregulation of endoplasmic reticulum (ER) stress-induced genes. Reduced expression of proteasome subunit alpha 7 (PSMA7) and acylaminoacyl peptide hydrolase (APEH) 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. O_FIG O_LINKSMALLFIG WIDTH=183 HEIGHT=200 SRC="FIGDIR/small/316810v2_ufig1.gif" ALT="Figure 1"> View larger version (71K): org.highwire.dtl.DTLVardef@d38d5borg.highwire.dtl.DTLVardef@e58513org.highwire.dtl.DTLVardef@83e274org.highwire.dtl.DTLVardef@884ec3_HPS_FORMAT_FIGEXP M_FIG C_FIG ImplicationsThis study identifies the novel links in the proteostasis network to target protein homeostasis in HGSOC. It recognizes the potential of inhibiting UCHL1 and APEH to sensitize cancer cells to proteotoxic stress and as novel alternative therapeutic approaches.