Poison cassette exon splicing of SRSF6 regulates nuclear speckle dispersal and the response to hypoxia

Hypoxia induces massive changes in alternative splicing (AS) to adapt cells to the lack of oxygen. Here, we identify the splicing factor SRSF6 as a key factor in the AS response to hypoxia. The SRSF6 level is strongly reduced in acute hypoxia, which serves a dual purpose: it allows for exon skipping and triggers the dispersal of nuclear speckles. Our data suggest that cells use dispersal of nuclear speckles to reprogram their gene expression during hypoxic adaptation and that SRSF6 plays an important role in cohesion of nuclear speckles. Down-regulation of SRSF6 is achieved through inclusion of a poison cassette exon (PCE) promoted by SRSF4. Removing the PCE 3 ' splice site using CRISPR/Cas9 abolishes SRSF6 reduction in hypoxia. Aberrantly high SRSF6 levels in hypoxia attenuate hypoxia-mediated AS and impair dispersal of nuclear speckles. As a consequence, proliferation and genomic instability are increased, while the stress response is suppressed. The SRSF4-PCE-SRSF6 hypoxia axis is active in different cancer types, and high SRSF6 expression in hypoxic tumors correlates with a poor prognosis. We propose that the ultra-conserved PCE of SRSF6 acts as a tumor suppressor and that its inclusion in hypoxia is crucial to reduce SRSF6 levels. This may prevent tumor cells from entering the metastatic route of hypoxia adaptation.

Automated summary

Hypoxia triggers significant changes in alternative splicing, and the splicing factor SRSF6 plays a crucial role in this response by regulating the inclusion of a poison cassette exon (PCE) through SRSF4. The reduction of SRSF6 levels in acute hypoxia promotes the dispersal of nuclear speckles, leading to the reprogramming of gene expression and hypoxic adaptation. Aberrantly high SRSF6 expression in hypoxia negatively affects alternative splicing and nuclear speckle dispersal, resulting in increased proliferation, genomic instability, and suppressed stress response. The SRSF4-PCE-SRSF6 hypoxia axis is active in different types of cancer, and high expression of SRSF6 in hypoxic tumors is associated with poor prognosis.