Abstract
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.
Highlights
The host microenvironment in which tumor cells are located may alter the original tumorigenic potential of these cells
We identified one antisense fragment that reduced MYB-binding protein 1a (MYBBP1A) protein expression by 50% and allowed the cells to grow under these restrictive conditions (Fig. S1B)
If the downregulation of MYBBP1A is an important trait required for the evolution of these cells, it must be maintained throughout tumor growth; we should be able to identify it in human tumors
Summary
The host microenvironment in which tumor cells are located may alter the original tumorigenic potential of these cells. The same cell located in a nonpermissive environment may not contribute to tumor growth. Impaired vascularization during early and later stages of tumor growth causes an altered microenvironment that lacks oxygen and nutrients, which greatly impairs the development of tumors (Carnero and Lleonart, 2016). In these cases, hypoxia has emerged as an essential factor for tumor physiology by promoting tumor initiation, progression, and resistance to therapy. Even in the presence of oxygen, cancer cells switch from generating ATP by the highly energy-efficient process of oxidative phosphorylation to the much less efficient process of glycolysis. We know that this metabolic switch, called the Warburg effect, is an important feature of cancer cells
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