A novel miR-206/hnRNPA1/PKM2 axis reshapes the Warburg effect to suppress colon cancer growth

Abstract

Alternative splicing of pyruvate kinase gene (PKM) results in a higher PKM2/PKM1 ratio that contributes to the Warburg effect and reversing the Warburg effect has opened novel avenues for cancer treatment. miR-206 functions as a tumor suppressor in several types of cancer. However, the effect and underlying mechanisms of miR-206 on the Warburg effect are not yet elucidated. Here, we showed that miR-206 expression was obviously decreased in CRC tissues based on LinkedOmics. A significant decrease in miR-206 expression was negatively correlated with advanced tumor stage, while inversely correlated with overall survival in CRC patients. Ectopic overexpression of miR-206 has dramatically restricted the cell proliferation, glucose consumption and lactate production in CRC cells, whereas transfection of miR-206 inhibitor exhibited the opposite results. Furthermore, miR-206 overexpression induced switching from PKM2 to PKM1 via modulating alternative splicing of PKM gene. The alternative splicing factor hnRNPA1 is identified as the direct functional target of miR-206. Mechanistically, miR-206 overexpression directly targeted hnRNPA1 to suppress PKM2 expression to attenuate Warburg effect and cell proliferation of CRC. Importantly, the restoration of hnRNPA1 expression mostly abrogated the miR-206-meditated Warburg effect. Collectively, these results revealed that the novel miR-206/hnRNPA1/PKM2 axis plays a pivotal role in the Warburg effect to modulate CRC progression.