JMJD2A promotes the Warburg effect and nasopharyngeal carcinoma progression by transactivating LDHA expression

Abstract

BackgroundJumonji C domain 2A (JMJD2A), as a histone demethylases, plays a vital role in tumorigenesis and progression. But, its functions and underlying mechanisms of JMJD2A in nasopharyngeal carcinoma (NPC) metabolism are remained to be clarified. In this study, we investigated glycolysis regulation by JMJD2A in NPC and the possible mechanism.MethodsJMJD2A expression was detected by Western blotting and Reverse transcription quantitative real-time PCR analysis. Then, we knocked down and ectopically expressed JMJD2A to detect changes in glycolytic enzymes. We also evaluated the impacts of JMJD2A-lactate dehydrogenase A (LDHA) signaling on NPC cell proliferation, migration and invasion. ChIP assays were used to test whether JMJD2A bound to the LDHA promoter. Finally, IHC was used to verify JMJD2A and LDHA expression in NPC tissue samples and analyze their correlation between expression and clinical features.ResultsJMJD2A was expressed at high levels in NPC tumor tissues and cell lines. Both JMJD2A and LDHA expression were positively correlated with the tumor stage, metastasis and clinical stage. Additionally, the level of JMJD2A was positively correlated with LDHA expression in NPC patients, and higher JMJD2A and LDHA expression predicted a worse prognosis. JMJD2A alteration did not influence most of glycolytic enzymes expression, with the exception of PFK-L, PGAM-1, LDHB and LDHA, and LDHA exhibited the greatest decrease in expression. JMJD2A silencing decreased LDHA expression and the intracellular ATP level and increased LDH activity, lactate production and glucose utilization, while JMJD2A overexpression produced the opposite results. Furthermore, JMJD2A could combine to LDHA promoter region and regulate LDHA expression at the level of transcription. Activated JMJD2A-LDHA signaling pathway promoted NPC cell proliferation, migration and invasion.ConclusionsJMJD2A regulated aerobic glycolysis by regulating LDHA expression. Therefore, the novel JMJD2A-LDHA signaling pathway could contribute to the Warburg effects in NPC progression.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3473-4) contains supplementary material, which is available to authorized users.

Identification of two HLA-A*0201 immunogenic epitopes of lactate dehydrogenase C (LDHC): potential novel targets for cancer immunotherapy

“…Hence, altered expression of LDHC could be involved in maintaining an alternative energy source by contributing to the metabolic switch in cancer cells. In addition, increased LDHA and decreased LDHB expressions facilitate tumor formation and progression through remodeling of the tumor microenvironment, increasing proliferation, and inducing epithelial-to-mesenchymal transition, cell migration and invasion, and angiogenesis [10][11][12][13][14][15][16][17][18][19][20]. In line with this, two studies to date demonstrate that enhanced expression of LDHC induces epithelial-to-mesenchymal transition, matrix metalloproteinase-9 (MMP9) expression and promotes cancer cell migration and invasion [7,21].…”

Unappreciated Role of LDHA and LDHB to Control Apoptosis and Autophagy in Tumor Cells

“…Thus, in many types of spontaneous cancers (e.g., pancreatic cancer, prostate cancer, gliomas and cutaneous melanoma metastases), an elevated LDHA expression is observed compared to normal tissues [22,23,24,25]. High levels of LDHA were confirmed also in gastric cancer (HER2 positive tumors have a significantly higher LDHA level than HER2 negative), and nasopharyngeal carcinoma [26,27]. Elevated levels of LDHA in tumor cells are considered as their metabolic adaptation to anaerobic glycolysis [23,24,25,26].…”

LDHA Promotes Oral Squamous Cell Carcinoma Progression Through Facilitating Glycolysis and Epithelial–Mesenchymal Transition

“…In the glycolytic pathway, lactate dehydrogenase A (LDHA) irreversibly catalyzes the conversion of pyruvate to lactate via the oxidative dehydrogenation of nicotinamide adenine dinucleotide (NADH) to NAD+. Several studies have reported that LDHA is highly expressed in various cancers such as pancreatic cancer, gastric, gallbladder, and breast cancers, as well as nasopharyngeal and hepatocellular carcinomas; its expression is positively correlated with the malignant progression of the cancers (9)(10)(11)(12)(13)(14)(15). However, the relationship between LDHA expression and the progression of OSCC, as well as the underlying mechanisms that affect the biological behavior of OSCC cells, are still unclear.…”