The pyruvate dehydrogenase complex in concert with the DNA/RNA-binding protein YBX1 regulates cell senescence and...

The activation of oncogenes is often accompanied by metabolic adaptations. The DNA/RNA-binding protein, Y-box binding protein 1 (YBX1), a well-known oncogene, is hyperactivated in nearly all cancer types. However, the metabolic hallmarks associated with YBX1 and the underlying mechanisms remain poorly understood. Here, we demonstrate that YBX1 sustains the activity of the pyruvate dehydrogenase (PDH) complex by regulating its catalytic alpha subunit, PDHA1. Mechanistically, YBX1 downregulates the expression of PDH kinases 1 and 4, leading to enhanced PDHA1 activity. Consequently, YBX1 deficiency results in significant impairment of pyruvate oxidation. Moreover, we found that YBX1, in conjunction with PDH activation, promotes epithelial cell senescence and suppresses cancer cell proliferation. These findings indicate that PDH activation imposes a constraint on the tumorigenic potential of YBX1.