The RUNX2 Transcription Factor Negatively Regulates SIRT6 Expression to Alter Glucose Metabolism in Breast Cancer Cells.
The RUNX2 Transcription Factor Negatively Regulates SIRT6 Expression to Alter Glucose Metabolism in Breast Cancer Cells.
复制标题
RUNX2转录因子负调节SIRT6表达以改变乳腺癌细胞中的葡萄糖代谢。
DOI：
10.1002/jcb.25171
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发表时间：
2015-10
影响因子：
4
通讯作者：
Passaniti A
中科院分区：
文献类型：
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作者：
Choe M;Brusgard JL;Chumsri S;Bhandary L;Zhao XF;Lu S;Goloubeva OG;Polster BM;Fiskum GM;Girnun GD;Kim MS;Passaniti A
促进有氧糖酵解和抑制线粒体氧化磷酸化的基因激活是癌症的标志之一。RUNX2转录因子介导乳腺癌（BC）骨转移并受葡萄糖可用性调节。但是，它调节葡萄糖代谢和促进致癌表型的机制尚不清楚。RUNX2在腔内BC细胞中的表达与雌激素受体-α (ERα)水平降低、锚定非依赖性生长、糖酵解基因表达、葡萄糖摄取增加以及对葡萄糖饥饿的敏感性相关，但与氧化磷酸化抑制剂无关。相反，RUNX2敲低在三阴性BC细胞抑制乳腺球形成和葡萄糖依赖。RUNX2敲低导致LDHA、HK2和GLUT1糖酵解基因表达降低，而丙酮酸脱氢酶a1 (PDHA1) mRNA和酶活性上调，这与糖酵解电位降低一致。nad依赖性组蛋白去乙酰化酶SIRT6是一种已知的肿瘤抑制因子，是这些runx2介导的代谢变化的关键调节因子。RUNX2的表达导致pAkt、HK2和PDHK1糖酵解蛋白水平升高，而SIRT6的异位表达降低了这些蛋白水平。RUNX2还抑制线粒体耗氧率（OCR），这是氧化磷酸化（呼吸）的一种衡量指标。在RUNX2阳性细胞中，SIRT6过表达可增加呼吸，而在RUNX2低表达细胞中，SIRT6敲低可减少呼吸。RUNX2在转录和翻译后水平均抑制SIRT6的表达，而在表达高水平RUNX2的恶性BC组织或细胞系中，内源性SIRT6的表达较低。这些结果支持了一种假设，即runx2介导的SIRT6肿瘤抑制因子的抑制调节了促进BC进展的代谢途径。
Activation of genes promoting aerobic glycolysis and suppression of mitochondrial oxidative phosphorylation is one of the hallmarks of cancer. The RUNX2 transcription factor mediates breast cancer (BC) metastasis to bone and is regulated by glucose availability. But, the mechanisms by which it regulates glucose metabolism and promotes an oncogenic phenotype are not known. RUNX2 expression in luminal BC cells correlated with lower estrogen receptor-α (ERα) levels, anchorage-independent growth, expression of glycolytic genes, increased glucose uptake, and sensitivity to glucose starvation, but not to inhibitors of oxidative phosphorylation. Conversely, RUNX2 knockdown in triple-negative BC cells inhibited mammosphere formation and glucose dependence. RUNX2 knockdown resulted in lower LDHA, HK2, and GLUT1 glycolytic gene expression, but upregulation of pyruvate dehydrogenase-A1 (PDHA1) mRNA and enzymatic activity, which was consistent with lower glycolytic potential. The NAD-dependent histone deacetylase, SIRT6, a known tumor suppressor, was a critical regulator of these RUNX2-mediated metabolic changes. RUNX2 expression resulted in elevated pAkt, HK2, and PDHK1 glycolytic protein levels that were reduced by ectopic expression of SIRT6. RUNX2 also repressed mitochondrial oxygen consumption rates (OCR), a measure of oxidative phosphorylation (respiration). Overexpression of SIRT6 increased respiration in RUNX2-positive cells, but knockdown of SIRT6 in cells expressing low RUNX2 decreased respiration. RUNX2 repressed SIRT6 expression at both the transcriptional and post-translational levels and endogenous SIRT6 expression was lower in malignant BC tissues or cell lines that expressed high levels of RUNX2. These results support a hypothesis whereby RUNX2-mediated repression of the SIRT6 tumor suppressor regulates metabolic pathways that promote BC progression.