Histone methyltransferase SETD1A interacts with HIF1? to enhance glycolysis and promote cancer progression in gastric cancer.

ABSTRACT: Growing tumors alter their metabolic profiles to support the increased cell proliferation. SETD1A, a histone lysine methyltransferase which specifically methylates H3K4, plays important roles in both normal cell and cancer cell functions. However, the function of SETD1A in gastric cancer (GC) progression and its role in GC metabolic reprogramming are still largely unknown. In the current study, we discovered that the expression of SETD1A was higher in GC tumor specimens compared to surrounding nontumor tissues. Upregulation of SETD1A increased GC cell proliferation, whereas downregulation of SETD1A inhibited GC cell proliferation. Furthermore, knockdown of SETD1A reduced glucose uptake and production of lactate and suppressed glycolysis by decreasing the expression of glycolytic genes, including GLUT1, HK2, PFK2, PKM2, LDHA, and MCT4. Mechanistically, SETD1A interacted with HIF1? to strengthen its transactivation, indicating that SETD1A promotes glycolysis through coactivation of HIF1?. SETD1A and HIF1? were recruited to the promoter of HK2 and PFK2, where SETD1A could methylate H3K4. However, knockdown of SETD1A decreased the methylation of H3K4 on HK2 and PFK2 promoter and reduced HIF1? recruitment necessary to promote transcription of glycolytic genes. Inhibition of HIF1? decelerated SETD1A-enhanced GC cell growth. In additional, there was a linear correlation between SETD1A and several key glycolytic genes in human GC specimens obtained from TCGA dataset. Thus, our results demonstrated that SETD1A interacted with HIF1? to promote glycolysis and accelerate GC progression, implicating that SETD1A may be a potential molecular target for GC treatment.

SUBMITTER: Wu J 

PROVIDER: S-EPMC7266269 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature