The Tumor Suppressor Roles of MYBBP1A, a Major Contributor to Metabolism Plasticity and Stemness

Abstract

The MYB binding protein 1A (MYBBP1A, also known as p160) acts as a co-repressor of multiple transcription factors involved in many physiological processes. Therefore, MYBBP1A acts as a tumor suppressor in multiple aspects related to cell physiology, most of them very relevant for tumorigenesis. We explored the different roles of MYBBP1A in different aspects of cancer, such as mitosis, cellular senescence, epigenetic regulation, cell cycle, metabolism plasticity and stemness. We especially reviewed the relationships between MYBBP1A, the inhibitory role it plays by binding and inactivating c-MYB and its regulation of PGC-1α, leading to an increase in the stemness and the tumor stem cell population. In addition, MYBBP1A causes the activation of PGC-1α directly and indirectly through c-MYB, inducing the metabolic change from glycolysis to oxidative phosphorylation (OXPHOS). Therefore, the combination of these two effects caused by the decreased expression of MYBBP1A provides a selective advantage to tumor cells. Interestingly, this only occurs in cells lacking pVHL. Finally, the loss of MYBBP1A occurs in 8%–9% of renal tumors. tumors, and this subpopulation could be studied as a possible target of therapies using inhibitors of mitochondrial respiration.

Growth of pancreatic cancers with hemizygous chromosomal 17p loss of MYBBP1A can be preferentially targeted by PARP inhibitors

“…Prior studies demonstrate conflicting roles for MYBBP1A in cancer (42). Specifically, loss of MYBBP1A was associated with decreased, increased, or unchanged growth of cancer cell types (20,23,(42)(43)(44).…”

“…Prior studies demonstrate conflicting roles for MYBBP1A in cancer ( 42 ). Specifically, loss of MYBBP1A was associated with decreased, increased, or unchanged growth of cancer cell types ( 20 , 23 , 42 – 44 ). Although it is possible that MYBBP1A may have cancer type–specific functions, the discrepancies in past studies can also be reconciled by the variable repression of MYBBP1A protein, as noted in Mori et al ( 21 ).…”

“…MYBBP1A has also been demonstrated to either promote or impair cell migration ( 20 , 42 ). The lack of any changes to cell migration in MYBBP1A hemizygous cells appears at odds with these prior studies, but this can be reconciled by the degree of MYBBP1A KD performed in prior studies as both prior studies achieved 80 to 90% reduction of MYBBP1A levels compared to the 50% reduction of MYBBP1A protein in MYBBP1A hemizygous cells.…”

NAD+ metabolism, stemness, the immune response, and cancer

“…Metabolic and oxidative stress have been suggested to be the cause of the resistance of CSCs to therapeutic treatment because of the metabolic plasticity induced in CSCs; however, these CSCs have also been reported to be highly sensitive to compounds that target mitochondrial metabolism. 76 , 322 – 324 Therefore, mitochondrial targeting of NAMPT activity may be used to avoid the toxicity observed in first-generation inhibitors and provide an enhanced therapeutic window. Cancer cells undergoing stress (for example, oxidative stress, glucose deprivation or hypoxia) generate the mitochondrial signaling molecule hydrogen sulfide (H 2 S), which has the ability to upregulate NAMPT.…”

Role of Mitochondria in Cancer Stem Cell Resistance

“…Mitochondrial biogenesis is finely tuned by cells, with multiple pathways or regulators, such as PGC-1α, MYBBP1a or the MAPK/ERK pathway, which can modify their activity [ 63 , 97 , 98 , 99 , 100 ]. PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-α) is an important regulator of the transcription of nuclear-encoded genes implicated in mitochondrial biogenesis [ 97 ].…”