SF3B1 facilitates HIF1-signaling and promotes malignancy in pancreatic cancer

• DOI: 10.1016/j.celrep.2022.111266
• Publication Date: 2022-08-23T14:36:26Z
• Authors: Patrik Simmler; Cédric Cortijo; Lisa Maria Koch; Patricia Galliker; Silvia Angori; Hella Anna Bolck; Christina Mueller; Ana Vukolic; Peter Mirtschink; Yann Christinat; Natalie R. Davidson; Kjong-Van Lehmann; Giovanni Pellegrini; Chantal Pauli; Daniela Lenggenhager; Ilaria Guccini; Till Ringel; Christian Hirt; Kim Fabiano Marquart; Moritz Schaefer; Gunnar Rätsch; Matthias Peter; Holger Moch; Markus Stoffel; Gerald Schwank
• Keywords: 0301 basic medicine; HIF1 transcription; pancreatic cancer; 10050 Institute of Pharmacology and Toxicology; 10184 Institute of Veterinary Pathology; 610 Medicine & health; hypoxia; glycolysis; HIF1 transcription; splicing; SF3B1; pancreatic cancer; chromophobe renal cell carcinoma; Mice; splicing; 03 medical and health sciences; 1300 General Biochemistry, Genetics and Molecular Biology; 10049 Institute of Pathology and Molecular Pathology; Cell Line, Tumor; Animals; Hypoxia; 0303 health sciences; chromophobe renal cell carcinoma; hypoxia; SF3B1; glycolysis; Hypoxia-Inducible Factor 1, alpha Subunit; Phosphoproteins; 3. Good health; Pancreatic Neoplasms; Hypoxia-Inducible Factor 1; RNA Splice Sites; RNA Splicing Factors; Signal Transduction

ISSN:2211-1247<br/>Cell Reports, 40 (8)<br/>ISSN:2666-3864<br/>Mutations in the splicing factor SF3B1 are frequently occurring in various cancers and drive tumor progression through the activation of cryptic splice sites in multiple genes. Recent studies also demonstrate a positive correlation between the expression levels of wild-type SF3B1 and tumor malignancy. Here, we demonstrate that SF3B1 is a hypoxia-inducible factor (HIF)-1 target gene that positively regulates HIF1 pathway activity. By physically interacting with HIF1α, SF3B1 facilitates binding of the HIF1 complex to hypoxia response elements (HREs) to activate target gene expression. To further validate the relevance of this mechanism for tumor progression, we show that a reduction in SF3B1 levels via monoallelic deletion of Sf3b1 impedes 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.<br/>