RNF19A couples tumour-intrinsic adaptation with immune suppression in castration-resistant prostate cancer and reveals sinomenine as a candidate intervention

Abstract

Castration-resistant prostate cancer (CRPC) is characterized by tumour-cell adaptation and an immunosuppressive microenvironment, yet the molecular regulators linking these processes remain incompletely defined. By integrating single-cell transcriptomic datasets from hormone-sensitive prostate cancer and CRPC, we identified the E3 ubiquitin ligase ring finger protein 19A ( RNF19A) as a CRPC-associated regulator enriched in basal-like epithelial cells. RNF19A depletion impaired prostate-cancer cell growth and tumour formation, increased apoptosis, and suppressed metabolic programmes related to ATP production and oxidative phosphorylation. Unbiased immunoprecipitation–mass spectrometry identified p53 as an RNF19A-interacting protein, and subsequent analyses showed that RNF19A promoted p53 ubiquitination and proteasome-dependent degradation, thereby supporting tumour-cell survival. RNF19A depletion also induced NF-κB- and inflammation-associated transcriptional programmes, suggesting that RNF19A may influence the inflammatory and immune-regulatory state of the tumour microenvironment. Spatial transcriptomic analysis showed that RNF19A-high tumour-like niches were associated with suppressive myeloid and exhausted-CD8-like programmes. Consistent with this observation, RELA was also identified as an RNF19A-interacting protein, and RNF19A promoted RELA ubiquitination and degradation, thereby restraining RELA-dependent NF-κB signalling, chemokine production and antigen-presentation-related programmes. Finally, structure-guided natural-product screening identified sinomenine as a candidate RNF19A-binding compound. Sinomenine bound recombinant RNF19A, reduced RNF19A abundance, inhibited prostate-cancer cell and patient-derived organoid growth, and suppressed xenograft growth. Together, these findings show that RNF19A sustains CRPC progression by promoting p53 and RELA degradation, thereby enhancing tumour-cell survival while limiting inflammatory and antigen-presentation-associated signalling. RNF19A therefore represents a potential therapeutic target in CRPC.

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