# PSMC6 regulation of ovarian cancer cisplatin resistance unravels a new mode for proteasome targeting

## TL;DR

This study shows that PSMC6, a proteasome subunit, contributes to ovarian cancer resistance to cisplatin and suggests it could be a new target for treatment.

## Contribution

The study identifies a novel mode of proteasome targeting through PSMC6 and its role in cisplatin resistance in ovarian cancer.

## Key findings

- PSMC6 levels correlate with tumor stage and reduced survival in ovarian cancer.
- PSMC6 knockdown reduces cell growth and cisplatin resistance in ovarian cancer cells.
- PSMC6 silencing increases ubiquitinated protein accumulation and alters ERK1/2 signaling.

## Abstract

Ovarian carcinoma has still a poor prognosis. CRISPR/Cas9 loss-of-function screen revealed a relationship between the PSMC6 proteasome subunit expression and survival of cisplatin-sensitive and -resistant ovarian carcinoma cells. Increased levels of PSMC6 were evidenced in multiple ovarian carcinoma cell lines versus normal cells. An association between PSMC6 levels and tumour stages as well as with a reduced progression-free survival was found. Since a PSMC6 interactome analysis evidenced limited knowledge on PSMC6 biology, mechanistic studies were carried out. PSMC6 knockdown indicated reduced cell growth and clonogenicity in cisplatin-sensitive IGROV-1 and -resistant IGROV-1/Pt1 cells, with a higher impact in resistant cells. This behaviour was accompanied by the accumulation of ubiquitinated proteins and down-regulation of ERK1/2 phosphorylation mediated by increased DUSP6. PSMC6 silencing increased sensitivity to cisplatin in IGROV-1/Pt1 cells as shown by clonogenic assay and 3D spheroids. Since PSMC6 knockdown did not change sensitivity to 20S and 19S proteasome inhibitors, we suggest a new mode of proteasome targeting by interference with a proteasome ATPase. Overall, a link between PSMC6 and ovarian carcinoma aggressiveness is envisioned, highlighting PSMC6 as a potential diagnostic and therapeutic target.