LncRNA EPB41L4A-AS1 regulates glycolysis and glutaminolysis by mediating nucleolar translocation of HDAC2Research in context

Background: LncRNAs have been found to be involved in various aspects of biological processes. In this study, we aimed to uncover the molecular mechanisms of lncRNA EPB41L4A-AS1 in regulating glycolysis and glutaminolysis in cancer cells. Methods: The expression of EPB41L4A-AS1 in cancer patients was analyzed in TCGA and GEO datasets. The level of cellular metabolism was determined by extracellular flux analyzer. The relationship between p53 and EPB41L4A-AS1 was explored by qRT-PCR, luciferase assay and ChIP assay. The interactions between EPB41L4A-AS1 and HDAC2 or NPM1 were determined by RNA immunoprecipitation, RNA pull-down assay and RNA-FISH- immunofluorescence. Findings: EPB41L4A-AS1 was a p53-regulated gene. Low expression and deletion of lncRNA EPB41L4A-AS1 were found in a variety of human cancers and associated with poor prognosis of cancer patients. Knock down EPB41L4A-AS1 expression triggered Warburg effect, demonstrated as increased aerobic glycolysis and glutaminolysis. EPB41L4A-AS1 interacted and colocalized with HDAC2 and NPM1 in nucleolus. Silencing EPB41L4A-AS1 reduced the interaction between HDAC2 and NPM1, released HDAC2 from nucleolus and increased its distribution in nucleoplasm, enhanced HDAC2 occupation on VHL and VDAC1 promoter regions, and finally accelerated glycolysis and glutaminolysis. Depletion of EPB41L4A-AS1 increased the sensitivity of tumor to glutaminase inhibitor in tumor therapy. Interpretation: EPB41L4A-AS1 functions as a repressor of the Warburg effect and plays important roles in metabolic reprogramming of cancer. Keywords: EPB41L4A-AS1, HDAC2, Glycolysis, Glutaminolysis, Cancer metabolis

Hypoxia-induced <i>MIR155</i> is a potent autophagy inducer by targeting multiple players in the MTOR pathway

<p>Hypoxia activates autophagy, an evolutionarily conserved cellular catabolic process. Dysfunction in the autophagy pathway has been implicated in an increasing number of human diseases, including cancer. Hypoxia induces upregulation of a specific set of microRNAs (miRNAs) in a variety of cell types. Here, we describe hypoxia-induced <i>MIR155</i> as a potent inducer of autophagy. Enforced expression of <i>MIR155</i> increases autophagic activity in human nasopharyngeal cancer and cervical cancer cells. Knocking down endogenous <i>MIR155</i> inhibits hypoxia-induced autophagy. We demonstrated that <i>MIR155</i> targets multiple players in MTOR signaling, including <i>RHEB</i>, <i>RICTOR,</i> and <i>RPS6KB2</i>. <i>MIR155</i> suppresses target-gene expression by directly interacting with their 3′ untranslated regions (UTRs), mutations of the binding sites abolish their <i>MIR155</i> responsiveness. Furthermore, by downregulating MTOR signaling, <i>MIR155</i> also attenuates cell proliferation and induces G₁/S cell cycle arrest. Collectively, these data present a new role for <i>MIR155</i> as a key regulator of autophagy via dysregulation of MTOR pathway.</p