# Splice-switching of the oncogenic BCS1L isoform suppresses ovarian cancer progression by disrupting mitochondrial function

## TL;DR

A new treatment approach for ovarian cancer involves targeting a specific protein isoform to disrupt mitochondrial function and stop tumor growth.

## Contribution

A splice-switching strategy using antisense oligonucleotides to target the BCS1L-L isoform is introduced as a novel therapeutic approach for ovarian cancer.

## Key findings

- BCS1L-L promotes oxidative phosphorylation and ATP production, essential for cancer cell survival.
- Splice-switch antisense oligonucleotides reduced BCS1L-L levels and impaired tumor growth in ovarian cancer.
- The splicing factor USP39 regulates BCS1L isoform production by promoting exon 2 inclusion.

## Abstract

Increasing evidences demonstrate that mitochondrial function is essential for cancer cell survival and metastasis. However, the role of mitochondrial metabolic reprogramming in ovarian cancer progression remains largely unknown. Here, we report that mitochondrial chaperone BCS1L generates two major alternative-spliced isoforms, a full-length isoform (BCS1L-L) and a short isoform lacking exon 2 (BCS1L-S). Interestingly, BCS1L-L is elevated in several human cancers, and it significantly increased oxidative phosphorylation and ATP production in the present work, which is required for the survival of cancer cells. In contrast, BCS1L-S was unable to localize to the mitochondria as BCS1L-L did, and this led to impaired metabolic function. Mechanistically, splicing factor USP39 promoted exon 2 inclusion, thus facilitating the generation of oncogenic BCS1L-L and, thereby, maintaining mitochondrial homeostasis and survival of ovarian cancer cells. Importantly, we developed splice-switch antisense oligonucleotides (ASOs) that successfully induced exon 2 skipping and decreased BCS1L-L abundance, resulting in impaired tumor growth. These findings suggest that targeting oncogenic BCS1L-L by ASOs is a novel approach for ovarian cancer treatment.