ArticleClinical and translational medicine2026
TMEM59L promotes neuroendocrine differentiation and enzalutamide resistance in prostate cancer by regulating MUC1/β-catenin/MYC axis.
Article in Clinical and translational medicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundEnzalutamide resistance in advanced prostate cancer often leads to treatment-induced neuroendocrine prostate cancer (t-NEPC), characterized by aggressive lineage plasticity. The molecular regulators governing neuroendocrine differentiation and phenotypic transition are not well understood. Here, we characterize the functional role of the transmembrane protein TMEM59L in driving PCa progression, lineage plasticity and therapeutic resistance.
methodsWe combined bulk RNA sequencing, single-cell RNA sequencing, and spatial transcriptomics datasets to assess TMEM59L expression patterns and their association with clinical features. We investigated the biological functions of TMEM59L using enzalutamide-resistant (EnzR) PCa cell lines in vitro and corresponding mouse xenograft models in vivo. Mechanistic interactions were elucidated through molecular assays, including co-immunoprecipitation (Co-IP), GST pull-down and molecular docking.
resultsTMEM59L expression is negatively regulated by androgen receptor (AR) signalling and markedly elevated in EnzR PCa tissues. In PCa cells, ectopic TMEM59L expression induced a neuroendocrine-like phenotype, enhanced stemness, promoted epithelial-mesenchymal transition (EMT) and conferred enzalutamide resistance. Conversely, TMEM59L depletion restored drug sensitivity and significantly suppressed EnzR tumour growth in vivo. Mechanistically, TMEM59L directly interacts with MUC1 to facilitate its nuclear accumulation, thereby activating the downstream β-catenin/MYC signalling axis. Importantly, pharmacological inhibition or genetic silencing of MUC1 effectively reversed TMEM59L-induced neuroendocrine differentiation, stemness and enzalutamide resistance.
conclusionsOur findings uncover a previously unrecognized TMEM59L/MUC1/β-catenin/MYC signalling cascade associated with neuroendocrine differentiation and enzalutamide resistance in PCa. Targeting this regulatory axis presents a promising therapeutic strategy to circumvent resistance to next-generation AR signalling inhibitors.
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