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May 8th, 2025
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The University of Texas MD Anderson Cancer Center
cancer biology
biorxiv

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

Wible, D. J.Open in Google Scholar•Li, W.Open in Google Scholar•Liu, X.Open in Google Scholar•Sebastian, M. M.Open in Google Scholar•Tang, D. G.Open in Google Scholar•Bratton, S. B.Open in Google Scholar

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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