p53 overrides <i>METTL5</i> loss-induced tumor suppression via mitochondrial respiration.

Abstract

The tumor suppressor p53 is pivotal in repressing tumorigenesis under physiological conditions. Paradoxically, we find that wild-type (WT) p53 plays an oncogenic role in relieving <i>METTL5</i> depletion-caused cancer regression by sustaining mitochondrial respiration. The methyltransferase METTL5 is upregulated in non-small cell lung cancer (NSCLC) and associated with advanced tumor grade and poor prognosis. Depletion of <i>METTL5</i> impairs NSCLC cell proliferation and migration in vitro and in vivo, with p53-null cells displaying enhanced sensitivity. While <i>METTL5</i>-depletion inhibits cytoplasmic translation in both p53-WT and p53-null cells, only cells lacking p53 exhibit severe tumor regression due to defective mitochondrial protein synthesis and consequent respiratory dysfunction. Mechanistically, p53 binds 5'UTR of <i>TOMM40</i>, the crucial gatekeeper of mitochondrial protein import, to enforce its exclusion from translation. <i>METTL5</i> loss promotes p53 nuclear retention via inhibiting MDM2-mediated p53 ubiquitination, alleviating its translational suppression of <i>TOMM40</i>, and supporting oxidative phosphorylation. Remarkably, the combination targeting of <i>p53</i> and <i>METTL5</i> synergistically attenuates the proliferation and migration in p53-WT cancer cells. Our study elucidates the essential role of p53 in supporting tumor viability upon <i>METTL5</i> deficiency by maintaining mitochondrial respiration. Meanwhile, it provides a molecular foundation for developing therapeutic strategies regarding cancers with WT p53.