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bioRxiv · 10.1101/2025.05.02.651776

Loss of ATG5 expression in a subset of human prostate cancers promotes tumor growth through accumulation of p62

Wible, D. J.·Li, W.·Liu, X.·Sebastian, M. M.·Tang, D. G.·Bratton, S. B.
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Abstract

Loss-of-function mutations in autophagy-related (ATG) genes are rare in cancer. However, we report herein that ATG5 is fully deleted in [~]14% of prostate cancers (PCa), rivaling that of well-established tumor suppressor genes. ATG5 expression was downregulated at both mRNA and protein levels and was associated with poor patient survival. The DU145 PCa cell line, isolated from a brain metastasis, is entirely deficient in ATG5; and while ATG5 reintroduction restored autophagy, it dramatically inhibited tumor growth in vivo and led to near complete consumption of the multifunctional autophagy receptor/signaling protein, p62. Deletion of SQSTM1 confirmed that p62 was essential for tumor growth; and Reverse Phase Protein Array analysis revealed that p62 protein was significantly increased in prostate tumors, despite a reduction in mRNA expression. Thus, ATG5 appears to function as a novel tumor suppressor in a subset of prostate tumors and does so, at least in part, through autophagic degradation of p62.

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Wible, D. J., Li, W., Liu, X., Sebastian, M. M., Tang, D. G., Bratton, S. B.. 2025-05-08. Loss of ATG5 expression in a subset of human prostate cancers promotes tumor growth through accumulation of p62. https://doi.org/10.1101/2025.05.02.651776

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