Identification of SRSF9 through pooled shRNA screening links BNIP3 splicing to autophagy and metabolic reprogramming in breast cancer.

ABSTRACT: Autophagy is a critical catabolic process that maintains cellular homeostasis, yet the role of alternative splicing in regulating hypoxia-induced autophagy remains largely unexplored. Here, through a pooled shRNA screen of RNA-binding proteins (RBPs) in hypoxic breast cancer cells, we identified the splicing factor SRSF9 as a key regulator. We found that SRSF9 expression is significantly reduced under hypoxia, while its restoration diminishes autophagosome formation. SRSF9 directly controls the alternative splicing of BNIP3 by binding to its third exon, generating two functionally distinct isoforms. The full-length isoform, BNIP3-FL, promotes canonical autophagy by interacting with the BCL-2-BECN1 complex. In contrast, the truncated isoform, BNIP3-Δ3, lacks this function and instead promot

SUBMITTER: Pandey A 

PROVIDER: S-EPMC12362092 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature