Suppression of miR‐199a maturation by HuR is crucial for hypoxia‐induced glycolytic switch in hepatocellular carcinoma

Abstract

Glucose metabolic reprogramming is a hallmark of cancer. Cancer cells rapidly adjust their energy source from oxidative phosphorylation to glycolytic metabolism in order to efficiently proliferate in a hypoxic environment, but the mechanism underlying this switch is still incompletely understood. Here, we report that hypoxia potently induces the RNA-binding protein HuR to specifically bind primary miR-199a transcript to block miR-199a maturation in hepatocellular carcinoma (HCC) cells. We demonstrate that this hypoxia-suppressed miR-199a plays a decisive role in limiting glycolysis in HCC cells by targeting hexokinase-2 (Hk2) and pyruvate kinase-M2 (Pkm2). Furthermore, systemically delivered cholesterol-modified agomiR-199a inhibits [(18)F]-fluorodeoxyglucose uptake and attenuates tumor growth in HCC tumor-bearing mice. These data reveal a novel mechanism of reprogramming of cancer energy metabolism in which HuR suppresses miR-199a maturation to link hypoxia to the Warburg effect and suggest a promising therapeutic strategy that targets miR-199a to interrupt cancerous aerobic glycolysis.

WITHDRAWN: Lack of miR-216b-5p, miR-33a-5p or miR-122-5p in MSCs exosomes promotes breast cancer glycolysis by targeting HK2, LDHA and PKM2

“…There was no significant difference for PKM2 mRNA in the breast cancer with miR-122-5p or the miRNA control transfection, but, PKM2 protein showed down-regulation in the cells. HK2 was regulated by miR-143 [24], miR-155 [25], miR-199a-5p [26], miR-29b [27,[28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43], miR-140-5p in various cancers like bladder cancer, liver cancer and prostate cancer. LDHA was regulated by miR-383, miR34a, miR-122, miR-30a-5p and other miRNAs in cancer.…”

Targeted delivery of microRNA‐199a‐3p using self‐assembled dipeptide nanoparticles efficiently reduces hepatocellular carcinoma in mice

“…The level of miR‐199a‐3p is consistently downregulated in HCC leading to regulation of the cell phenotype by targeting tyrosine protein kinase Met (c‐Met) and the mechanistic target of rapamycin (mTOR) and serine/threonine‐protein kinase 4 (PAK4) . Ectopic expression of miR‐199a‐3p resulted in suppression of HCC growth both in vitro and in vivo . Clinical success of miRNA therapeutics has been limited due to their intrinsic issues like sensitivity towards nuclease degradation, large molecular weight, polyanionic charge, non‐specificity and off target side effects .…”

Posttranscriptional regulation ofFOXOexpression: microRNAs and beyond

“…In addition to the direct removal of miRNAs/miRISCs by HuR from the 3′‐UTR of a given mRNA, a second level of miRNA regulation by HuR has recently been described. HuR can bind primary transcripts of specific miRNA genes, thus inhibiting their processing and formation of mature miRNA (Lebedeva et al , ; Choudhury et al , ; Zhang et al , ). For instance, HuR, in complex with Musashi homolog 2 protein, suppresses maturation of miR‐7 in non‐neural cells (Lebedeva et al , ; Choudhury et al , ).…”

“…For instance, HuR, in complex with Musashi homolog 2 protein, suppresses maturation of miR‐7 in non‐neural cells (Lebedeva et al , ; Choudhury et al , ). Moreover, maturation of miR‐199a is suppressed by HuR in hepatocellular carcinoma cells under hypoxic conditions, which contributes to the cancer cell switch to glycolytic metabolism (Zhang et al , ).…”