c-MYB- and PGC1a-dependent metabolic switch induced by MYBBP1A loss in renal cancer
c-MYB- and PGC1a-dependent metabolic switch induced by MYBBP1A loss in renal cancer
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DOI：
10.1002/1878-0261.12499
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发表时间：
2019-07-01
影响因子：
6.6
通讯作者：
Carnero, Amancio
中科院分区：
文献类型：
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作者：
Felipe-Abrio, Blanca;Verdugo-Sivianes, Eva M.;Carnero, Amancio
肿瘤微环境可能改变肿瘤细胞原有的致瘤潜能。在恶劣的环境条件下，赋予选择性优势的基因改变可能启动肿瘤亚克隆的生长，为这些肿瘤的生长提供新的机会。我们进行了基因功能丧失筛查，以确定在没有葡萄糖的情况下能够促进肿瘤细胞生长的基因改变。我们发现，在不允许的条件下，MYBBP1A的下调会增加肿瘤的致癌特性。MYBBP1a的下调可通过减轻直接抑制和通过c-myb增加PGC1α的mRNA水平间接地同时激活PGC1α，导致代谢从糖酵解转变为OXPHOS，并在低糖微环境中增加肿瘤的发生。我们还发现MYBBP1A在人类肾肿瘤样本中的表达降低，这表明参与氧化代谢的基因表达水平很高。综上所述，我们的数据支持MYBBP1A通过调节c-MYB和PGC1α作为肿瘤抑制因子的作用。因此，MYBBP1A的缺失通过代谢开关增加了肿瘤的适应性。
The tumor microenvironment may alter the original tumorigenic potential of tumor cells. Under harsh environmental conditions, genetic alterations conferring selective advantages may initiate the growth of tumor subclones, providing new opportunities for these tumors to grow. We performed a genetic loss-of-function screen to identify genetic alterations able to promote tumor cell growth in the absence of glucose. We identified that downregulation of MYBBP1A increases tumorigenic properties under nonpermissive conditions. MYBBP1A downregulation simultaneously activates PGC1 alpha, directly by alleviating direct repression and indirectly by increasing PGC1 alpha mRNA levels through c-MYB, leading to a metabolic switch from glycolysis to OXPHOS and increased tumorigenesis in low-glucose microenvironments. We have also identified reduced MYBBP1A expression in human renal tumor samples, which show high expression levels of genes involved in oxidative metabolism. In summary, our data support the role of MYBBP1A as a tumor suppressor by regulating c-MYB and PGC1 alpha. Therefore, loss of MYBBP1A increases adaptability spanning of tumors through metabolic switch.