MAOB promotes ROS-mediated DNA damage, triggering a cyclic MAOB-HNF1A-53BP1-p53 axis that suppresses the malignancy of clear cell renal cell carcinoma

Monoamine oxidases (MAOA and MAOB) are mitochondrial enzymes that degrade various monoamine neurotransmitters, which have been recognized as important regulators of tumor progression. Recently, conflicting roles of both enzymes were identified in several cancer types. However, their potential involvement in the progression of clear cell renal cell carcinoma (ccRCC) remains unclear. In this study, in silico analysis of the TCGA-KIRC dataset revealed that MAOB has a more significant prognostic impact than MAOA and serves as an independent prognostic factor for overall survival in ccRCC. Lower MAOB transcript and protein levels were observed in RCC tissues compared to normal tissues and were associated with larger tumor sizes. Enzymatically active MAOB promoted reactive oxygen species (ROS)-induced DNA damage, subsequently enhancing the stability and transcriptional activity of p53, which induced G1 cell cycle arrest, mitochondria apoptosis, and lipid peroxidation-triggered ferroptosis, ultimately suppressing tumor growth both in vitro and in vivo. Molecular studies showed that MAOB stabilizes and activates p53 through post-translational modifications (PTMs), including increased phosphorylation at Ser15 and acetylation at Lys382, as well as activation of the hepatocyte nuclear factor 1 homeobox A (HNF1A)-p53-binding protein 1 (53BP1) axis. Activated p53, in turn, regulated MAOB through positive feedback. Clinically, ccRCC samples revealed a positive correlation between MAOB and HNF1A expression, with patients expressing high levels of both having the best prognoses. Regarding therapeutic aspects, we discovered that DNA methyltransferase inhibitors serve as potential MAOB inducer in ccRCC. The current findings reveal novel mechanisms by which MAOB suppresses the malignancy of ccRCC and suggest that MAOB may serve as a valuable prognostic marker in the management of ccRCC.