Nutrient deprivation promotes bladder cancer metastasis through Beclin-1 deacetylation-mediated autophagy activation

Deprivation of nutrients in the tumor microenvironment drives malignant progression, yet the molecular mechanisms linking metabolic stress to metastasis in bladder Cancer remain incompletely understood. Here, we report that nutrient-deprivation stress promotes metastasis by orchestrating a post-translational modification cascade centered on Beclin-1. Clinical analysis revealed that acetylation of Beclin-1 at lysine residues K430 and K437 was significantly reduced in muscle-invasive bladder Cancer (MIBC) compared with non-muscle-invasive bladder Cancer (NMIBC), a molecular signature inversely correlated with elevated phospho-eIF2α, a marker of cellular starvation. Mechanistically, nutrient deprivation dynamically regulates the expression of the deacetylase SIRT1 and acetyltransferase p300, shifting the balance toward Beclin-1 deacetylation. This deacetylation event serves a dual function: it enhances Beclin-1 protein stability by shielding it from TRIM21-mediated K48-linked ubiquitination and proteasomal degradation, and it promotes autophagosome formation by strengthening its interaction with pro-autophagic partners Vps34, ATG14, and UVRAG while weakening its binding to the inhibitor Rubicon. Consequently, this leads to sustained Autophagy activation and epithelial-mesenchymal transition. Genetic and pharmacological interventions further confirmed the central role of this axis, demonstrating that SIRT1 activation by resveratrol promoted metastasis, whereas p300 activation by CTB suppressed it. Crucially, these effects were abrogated in cells expressing deacetylation-mimetic Beclin-1 mutants, suggesting a direct causal link. Our study unveils the SIRT1/p300-Beclin-1-TRIM21 axis as a key nutrient-sensing pathway that promotes bladder Cancer metastasis through crosstalk between acetylation and ubiquitination. These findings identify new therapeutic vulnerabilities in advanced bladder Cancer.

Acetylation; Autophagy; Bladder cancer; Nutrient deprivation; Ubiquitination.