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

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.