SF3B1 facilitates HIF1-signaling and promotes malignancy in pancreatic cancer

Mutations in the splicing factor SF3B1 are frequently occurring in various cancers and drive tumor progres-sion through the activation of cryptic splice sites in multiple genes. Recent studies also demonstrate a pos-itive correlation between the expression levels of wild-type SF3B1 and tumor malignancy. Here, we demon-strate that SF3B1 is a hypoxia-inducible factor (HIF)-1 target gene that positively regulates HIF1 pathway activity. By physically interacting with HIF1a, SF3B1 facilitates binding of the HIF1 complex to hypoxia response elements (HREs) to activate target gene expression. To further validate the relevance of this mech-anism for tumor progression, we show that a reduction in SF3B1 levels via monoallelic deletion of Sf3b1 im-pedes tumor formation and progression via impaired HIF signaling in a mouse model for pancreatic cancer. Our work uncovers an essential role of SF3B1 in HIF1 signaling, thereby providing a potential explanation for the link between high SF3B1 expression and aggressiveness of solid tumors.

Automated summary

Mutations in the splicing factor SF3B1 are frequently occurring in various cancers and drive tumor progression. This study demonstrates that SF3B1 is a target gene of HIF1 and positively regulates HIF1 pathway activity by facilitating the binding of HIF1 complex to HREs. The reduction in SF3B1 levels impede tumor formation and progression via impaired HIF signaling in a mouse model for pancreatic cancer.