MicroRNA-26a regulates glucose metabolism by direct targeting PDHX in colorectal cancer cells

Abstract

BackgroundReprogramming energy metabolism has been an emerging hallmark of cancer cells. MicroRNAs play important roles in glucose metabolism.MethodsThe targets of microRNA-26a (miR-26a) were predicted by bioinformatics tools. The efficacy of miR-26a binding the 3′-untranslated region (UTR) of pyruvate dehydrogenase protein X component (PDHX) mRNA was evaluated using a dual-luciferase reporter assay. The PDHX expression at the mRNA and protein level in several colon cancer cell lines was quantified with real-time PCR and Western blot analysis respectively. The effects of miR-26a on glucose metabolism were determined by detecting the content of glucose consumption, production of lactate, pyruvate, and acetyl-coenzyme A.ResultsThe expression of miR-26a is inversely associated with the level of its targeting protein PDHX in several colon cancer cell lines with different malignancy potentials. MiR-26a inhibits PDHX expression by direct targeting the 3′-UTR of PDHX mRNA. The glucose consumption and lactate concentration were both greatly increased in colon cancer cells than the normal colon mucosal epithelia under physiological conditions. The overexpression of miR-26a in HCT116 cells efficiently improved the accumulation of pyruvate and decreased the production of acetyl coenzyme A. Meanwhile the inhibition of miR-26a expression induced inverse biological effects.ConclusionsMiR-26a regulates glucose metabolism of colorectal cancer cells by direct targeting the PDHX, which inhibits the conversion of pyruvate to acetyl coenzyme A in the citric acid cycle.

MiR-26a downregulates retinoblastoma in colorectal cancer

“…This apparent discrepancy renders miRNA regulation even more astonishing, as it suggests that a given miRNAmRNA interaction is not oncogenic or tumor suppressing per se, but can have either outcome depending on the context. The evidence that we present here, together with the targeting of PDHX, 17 highlights the importance of this miRNA as an oncogenic regulator in CRC.…”

“…And this function, together with the previously observed regulation of glucose metabolism through PDHX targeting, 17 accentuates the importance of miR-26a as a multifunctional regulator in colorectal carcinogenesis.…”

“…16 These data show that the particular function of miR-26a in CRC development cannot be inferred, but must be analyzed directly. Currently, it is known that it targets PDHX and modifies glucose metabolism, 17 but whether it actually targets known CRC-related genes such as PTEN, GSK3A, and Rb1 in CRC development remains to be explored; in this article, we do so with the miR-26a Rb1 interaction.…”

MicroRNA-26a: An Emerging Regulator of Renal Biology and Disease

“…There are two different nucleotides between the mature sequences of miR-26a and miR-26b, whereas miR-26a-1 and miR-26a-2 have fully identical sequences arising from the 5’ arm of the respective precursors [40]. Plenty of publications reported that miR-26a plays an important role in various diseases [41-43], and most of them focused on cancer or cancer-related diseases, including colorectal, breast, ovarian, and gastric cancers [42, 44-47]. For example, miR-26a promotes cell proliferation and apoptosis by targeting phosphatase and tensin homolog ( PTEN ), Cyclin D1, and Bcl-2 in cancer cells [48-50].…”

Noncoding RNAs in Regulation of Cancer Metabolic Reprogramming

“…One of the strategies that cancer cells use to achieve glycolytic switch is through controlling PDHX and PDK. It has been reported that miR-26a targets PDHX in colorectal cancer cells [ 98 ] and that miR-375 regulates cell survival by targeting PDK1 in gastric carcinomas [ 99 ]. Interestingly, another powerful microRNA, miR-34a, targets many glycolytic enzymes including HK1, HK2, LDHA and GPI, as well as PDK1 [ 100 , 101 ].…”