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 PGC1α, directly by alleviating direct repression and indirectly by increasing PGC1α 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 PGC1α. Therefore, loss of MYBBP1A increases adaptability spanning of tumors through metabolic switch.

中文翻译：

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肾癌中MYBBP1A缺失引起的c-MYB和PGC1a依赖性代谢转换。

肿瘤微环境可改变肿瘤细胞的原始致瘤潜力。在恶劣的环境条件下，赋予选择性优势的遗传改变可能会引发肿瘤亚克隆的生长，为这些肿瘤的生长提供新的机会。我们进行了遗传功能丧失筛选，以鉴定在葡萄糖不存在的情况下能够促进肿瘤细胞生长的遗传改变。我们发现，MYBBP1A的下调会增加非许可条件下的致瘤特性。MYBBP1A的下调同时通过直接抑制直接抑制而直接激活PGC1α，并通过c-MYB通过增加PGC1αmRNA水平间接激活PGC1α，从而导致在低糖微环境中从糖酵解转变为OXPHOS并增加了肿瘤的发生。我们还发现人肾肿瘤样品中MYBBP1A的表达降低，显示出参与氧化代谢的基因的高表达水平。总之，我们的数据通过调节c-MYB和PGC1α来支持MYBBP1A作为肿瘤抑制物的作用。因此，MYBBP1A的丢失通过代谢转换增加了肿瘤的适应性跨度。