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 HIF1α to strengthen its transactivation, indicating that SETD1A promotes glycolysis through coactivation of HIF1α. SETD1A and HIF1α 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 HIF1α recruitment necessary to promote transcription of glycolytic genes. Inhibition of HIF1α 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 HIF1α to promote glycolysis and accelerate GC progression, implicating that SETD1A may be a potential molecular target for GC treatment.
Highlights
Gastric cancer (GC) is the third leading cause of cancer-associated death among the world (Bray et al., 2018) and the second leading cause of cancer-associated death in China (Chen et al, 2016)
The western blot results showed that the expression of SETD1A was markedly higher in human GC specimens compared with nontumorous tissues (Fig. 1A)
Previous data have indicated SETD1A could assist hypoxia-inducible factor 1a (HIF1a) to enhance the HRE reporter activity; we examined whether HIF1a and SETD1A could recruit to the hypoxia response element (HRE) on the promoter of HIF1aregulated glycolytic genes hexokinase 2 (HK2) and PFK2
Summary
Gastric cancer (GC) is the third leading cause of cancer-associated death among the world (Bray et al., 2018) and the second leading cause of cancer-associated death in China (Chen et al, 2016). Though the main treatments for GC include surgery, targeted therapy, chemotherapy, and radiotherapy, the prognosis of Abbreviations CCK-8, cell counting kit-8; ChIP, chromatin immunoprecipitation; co-IP, co-immunoprecipitation; GC, gastric cancer; GLUT1, glucose transporter type 1; HIF1a, hypoxia-inducible factor 1 subunit alpha; HK2, hexokinase 2; HRE, hypoxia response element; KMT, lysine methyltransferase; LDHA, lactate dehydrogenase A; MCT4, monocarboxylate transporter 4; PFK2, 6-phosphofructo-2-kinase; PKM2, pyruvate kinase M2; RT-qPCR, real-time quantitative polymerase chain reaction; TCGA, The Cancer Genome Atlas; TNM, tumor node metastasis. Molecular Oncology 14 (2020) 1397–1409 a 2020 The Authors.
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