Journal Article

SF3B1 mutation in pancreatic cancer contributes to aerobic glycolysis and tumor growth through a PP2A–c‐Myc axis

Jiang, Shu‐Heng, Zhang, Jun‐Feng, Liu, Wei, He, Rui‐Zhe, Yang, Min‐Wei, Shen, Yang, Liu, De‐Jun, Fu, Xue‐Liang, Sun, Yong‐Wei, Yang, Jian‐Yu, Hua, Rong, Huo, Yan‐Miao, Tao, Ling‐Ye

2021

Overview

Hot spot gene mutations in splicing factor 3b subunit 1 (SF3B1) are observed in many types of cancer and create abundant aberrant mRNA splicing, which is profoundly implicated in tumorigenesis. Here, we identified that the SF3B1 K700E (SF3B1K700E) mutation is strongly associated with tumor growth in pancreatic ductal adenocarcinoma (PDAC). Knockdown of SF3B1 significantly retarded cell proliferation and tumor growth in a cell line (Panc05.04) with the SF3B1K700E mutation. However, SF3B1 knockdown had no notable effect on cell proliferation in two cell lines (BxPC3 and AsPC1) carrying wild‐type SF3B1. Ectopic expression of SF3B1K700E but not SF3B1WT in SF3B1‐knockout Panc05.04 cells largely restored the inhibitory role induced by SF3B1 knockdown. Introduction of the SF3B1K700E mutation in BxPC3 and AsPC1 cells also boosted cell proliferation. Gene set enrichment analysis demonstrated a close correlation between SF3B1 mutation and aerobic glycolysis. Functional analyses showed that the SF3B1K700E mutation promoted tumor glycolysis, as evidenced by glucose consumption, lactate release, and extracellular acidification rate. Mechanistically, the SF3B1 mutation promoted the aberrant splicing of PPP2R5A and led to the activation of the glycolytic regulator c‐Myc via post‐translational regulation. Pharmacological activation of PP2A with FTY‐720 markedly compromised the growth advantage induced by the SF3B1K700E mutation in vitro and in vivo. Taken together, our data suggest a novel function for SF3B1 mutation in the Warburg effect, and this finding may offer a potential therapeutic strategy against PDAC with the SF3B1K700E mutation. SF3B1 mutations have been previously implicated in tumorigenesis. Here, we investigate the role of SF3B1K700E mutation in pancreatic ductal adenocarcinoma (PDAC). SF3B1K700E led to aberrant splicing of PPP2R5A, coupled with c‐Myc activation higher aerobic glycolysis rate and growth advantage of tumor cells. Taken together, our data describe a novel function for SF3B1 K700E mutations in the Warburg effect. Inhibition of SF3B1 K700E mutation may potentially serve as a novel therapeutic strategy for patients with PDAC.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Acidification / Adenocarcinoma / Antibodies / Binding sites / Carcinoma, Pancreatic Ductal - genetics / Carcinoma, Pancreatic Ductal - metabolism / Cell growth / Cell Line, Tumor / Cell proliferation / Ectopic expression / Gene set enrichment analysis / Genes / Genetic aspects / Genomes / Glucose / Glucose metabolism / Glycolysis / Glycolysis - genetics / Health aspects / Hematology / Humans / Lactic acid / Medical research / mRNA / Mutation / Mutation - genetics / Myc protein / Pancreatic cancer / pancreatic ductal adenocarcinoma / Pancreatic Neoplasms - pathology / Phosphoproteins - metabolism / Plasmids / Polymerase chain reaction / PP2A / Proteins / Reagents / RNA / RNA Splicing / RNA Splicing Factors - genetics / RNA Splicing Factors - metabolism / SF3B1 / splicing factor / Splicing factors / Tumorigenesis / Tumors / Warburg effect