HDAC10 preserves genome stability by regulating PCM1 and p53 through chaperone-mediated autophagy

Genomic instability promotes malignant evolution in cancer, whereas DNA-damage-induced senescence acts as a barrier to the propagation of cells with chromosome abnormalities. Disruption of these protective responses permits the persistence and selection of genetically abnormal clones. Here, we show that HDAC10 deficiency induces chaperone-mediated autophagy dependent degradation of PCM1 and p53, compromising chromosome stability and senescence-associated growth restraint, respectively. Supporting clinical relevance, breast cancer datasets associated higher HDAC10 expression with favorable patient survival, revealed an inverse correlation between HDAC10 and LAMP2 expression, and showed a reciprocal pattern of higher HDAC10 and lower LAMP2 expression in patients responding to DNA damaging anthracycline chemotherapy. Our findings identify HDAC10 as a regulator linking CMA-dependent proteostasis to genome stability and cellular senescence. By preserving PCM1 and p53, HDAC10 supports mitotic fidelity and p53-dependent senescence, thereby limiting chromosome instability and the persistence of genomically unstable cells. Disruption of this regulatory axis therefore provides a mechanism by which chromosome instability and impaired senescence cooperate during malignant progression in breast cancer.