Data from Low Glucose–Induced Overexpression of <i>HOXC-AS3</i> Promotes Metabolic Reprogramming of Breast Cancer

Abstract

<div>Abstract<p>Breast cancer is the most common malignancy in women worldwide. However, the mechanisms underlying breast cancer energy metabolism and progression remain obscure. Cancer cells rapidly adapt to microenvironments with fluctuating nutrient levels. Here, we characterized a long noncoding RNA (lncRNA), <i>HOXC-AS3</i>, which is activated upon glucose deprivation to trigger a nutrient-stress response and a switch in glucose metabolism. Upregulation of <i>HOXC-AS3</i> in breast cancer was identified by in published microarray and RNA-sequencing datasets, and then confirmed by qRT-PCR in fresh breast cancer tissues. Glucose deprivation induced <i>HOXC-AS3</i> overexpression in a dose- and time-dependent manner in breast cancer cells. Gain- and loss-of-function experiments <i>in vitro</i> and <i>in vivo</i> showed that <i>HOXC-AS3</i> triggers energy metabolism reprogramming. ChIRP-mass spectrometry and unique molecular identifier RNA immunoprecipitation and high-throughput sequencing (UMI RIP-seq) identified binding motifs of <i>HOXC-AS3</i> with SIRT6. <i>HOXC-AS3</i> selectively antagonized SIRT6-mediated H3K9ac deacetylation of glycolysis-related genes. Moreover, <i>HOXC-AS3</i> binding to SIRT6 prevented contact inhibition of HIF1α, leading to reprogramming of metabolic pathways. In addition, <i>HOXC-AS3</i>, SP1, and <i>miR-1224–5p</i> formed a positive feedback loop to maintain cancer-promoting signals. Furthermore, administration of anti-<i>HOXC-AS3</i>-motif-RNAs effectively blocked the function of <i>HOXC-AS3</i>, ultimately suppressing breast cancer progression. These results reveal a critical role for <i>HOXC-AS3</i> in regulating the metabolic reprogramming of breast cancer cells under metabolic stress. Use of an anti-<i>HOXC-AS3</i>-motif RNA mixture may be a promising strategy to suppress breast cancer progression.</p>Significance:<p><i>HOXC-AS3</i> is a low glucose–activated long noncoding RNA that triggers metabolic reprogramming in breast cancer cells to adapt to nutrient stress, identifying <i>HOXC-AS3</i> as a potential therapeutic target for breast cancer treatment.</p></div>