HIF-1α Mediates Functional Switching of TGF-Β Signaling by Regulating the PKM mRNA Splicing and Metabolic Reprogramming in Non-Small Cell Lung Cancer

Abstract

Most cancer cells have fundamentally different metabolic characteristics, and in particular much higher rates of glycolysis and hypoxia than normal tissues, which support the increased demand for biosynthesis and promote tumor progression. Here, we found that transforming growth factor (TGF)-β plays a dual function in regulating glycolysis and cell proliferation in non-small cell lung cancer. We discovered that TGF-β could slightly inhibit glycolysis under normoxia while it significantly promoted glycolysis of tumor cells under hypoxia in vitro and in vivo. The binding of hypoxia-inducible factor (HIF)-1 α to the MH2 domain of phosphorylated Smad3 switched TGF-β function to glycolysis by changing Smad partners under hypoxia. The Smad-p107-E2F4/5 complex that initially inhibited c-Myc expression was transformed into a Smad-HIF-1α complex that promoted the expression of c-Myc. The increased expression of c-Myc promoted alternative splicing of PKM to PKM2, resulting in the metabolic reprogramming of tumor cells. In addition, the TGF-β/Smad signal lost its effect on cell cycle regulatory protein p15/p21. Furthermore, high expression of c-Myc inhibited the expression of p15/p21 and promoted the proliferation of tumor cells under hypoxia. Our results indicated that HIF-1α functions as a critical factor in the dual role of TGF-β in tumor cells, and may be used as a biomarker or therapeutic target for TGF-β mediated cancer progression.