促肿瘤长链非编码RNA LINC00973通过增强LDHA酶活促进肿瘤细胞有氧糖酵解

Oncogenic lncRNA LINC00973 promotes Warburg effect by enhancing LDHA enzyme activity

有氧糖酵解在肿瘤细胞内被特异激活的调控机制尚不清楚.本研究通过大规模的功能筛选,发现了一个能显著促肿瘤细胞增殖的长链非编码RNA LINC00973.敲低该RNA的表达,能够抑制多种肿瘤细胞的体外增殖及体内(动物)生长.LINC00973能够结合到糖酵解关键酶LDHA(乳酸脱氢酶A)上并增强其酶活,进而加速肿瘤细胞的有氧糖酵解,最终促进肿瘤细胞增殖.LINC00973在多种肿瘤的样本中显著高表达,且高表达LINC00973的病人预后较差.本研究提示在肿瘤细胞中高表达的LINC00973促进了肿瘤细胞中的有氧糖酵解的特异激活,揭示了肿瘤细胞中特异存在的糖酵解调控方式,为靶向糖酵解开发广谱抗肿瘤药物提供了新靶标.

Aerobic glycolysis,also known as the Warburg effect,is a hallmark of cancer and essential for metabolism in malignancies,but its regulation and modulation in cancer cells remain poorly understood.Here,using large-scale functional screening,we identified a tumor-associated and broadly expressed oncogenic long noncoding RNA LINC00973.Notably,knocking down LINC00973 significantly inhibits the proliferation of multiple types of cancer cells and reduces tumor growth in vivo.Mechanistically,LINC00973 directly binds to lactate dehydrogenase A(LDHA),an essential glycolytic enzyme,and enhances its enzymatic activity,thereby promoting glycolysis.Clinically,high expression of LINC00973 is significantly associated with poor prognosis in many types of human cancers.This work demonstrates that LINC00973 modulates cancer-specific regulation of the Warburg effect,and may represent a potential target for broad-acting anti-cancer therapies.