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Targeting PRAME directly or via EZH2 inhibition overcomes retinoid resistance and represents a novel therapy for keratinocyte carcinoma.

Brandon Ramchatesingh·Amelia Martinez Villarreal·Philippe Lefrançois·Jennifer Gantchev·Sriraam Sivachandran·Samy Abou Setah·Ivan V Litvinov
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Abstract

Retinoids have demonstrated efficacy as preventative/treatment agents for keratinocyte carcinomas (KCs): basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (SCC). However, retinoid resistance mechanisms limit the efficacy of these compounds. A subset of KCs expresses Preferentially Expressed Antigen in Melanoma (PRAME): a retinoid signaling corepressor. PRAME is proposed to repress retinoid signaling by guiding enhancer of zeste homolog 2 (EZH2) to retinoic acid response elements (RARE) in promoters. We investigated the effects of PRAME on KC pathogenesis and retinoid response. High-PRAME expression in tumors was negatively correlated with epidermal differentiation gene signatures. PRAME overexpression downregulated epidermal differentiation gene signatures and impaired differentiation in 3D culture. PRAME overexpression attenuated retinoid-induced RARE activation, growth suppression, and differentiation responses. Conversely, low-PRAME tumors and PRAME-depleted KC cells demonstrated enriched epidermal differentiation gene signatures. PRAME downregulation restored retinoid-induced RARE activation, growth suppression, keratinization in SCC, and cell death signaling in BCC. Furthermore, combined retinoid and EZH2 inhibitor treatment augmented RARE activation and suppressed PRAME-expressing KC cell growth. Hence, PRAME confers retinoid resistance in KC, which may be overcome by EZH2 inhibition.

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Enhancer of Zeste Homolog 2 ProteinAntigens, NeoplasmRetinoidsSkin NeoplasmsKeratinocytesBasal Cell CarcinomaCarcinoma, Squamous CellHumansCell Line, TumorResponse ElementsTranscriptomeDrug Resistance, NeoplasmEZH2PRAMEbasal cell carcinomacutaneous squamous cell carcinomaretinoid resistanceretinoidsJournal ArticleResearch Support, Non-U.S. Gov't

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Brandon Ramchatesingh, Amelia Martinez Villarreal, Philippe Lefrançois, Jennifer Gantchev, Sriraam Sivachandran, Samy Abou Setah, Ivan V Litvinov. 2025-03-18. Targeting PRAME directly or via EZH2 inhibition overcomes retinoid resistance and represents a novel therapy for keratinocyte carcinoma.. https://doi.org/10.1002/1878-0261.13820

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EZH2 Suppression Diversifies Prostate Cancer Lineage Variant Evolution and Lacks Efficacy in Inhibiting Disease Progression.

UNLABELLED: Advanced prostate cancer remains a leading cause of cancer-related death among men due to disease progression in nearly all patients on standard-of-care therapy targeting the androgen receptor. An important mechanism driving therapeutic resistance is lineage plasticity, which enables prostate cancer cells to reprogram into lineage variants no longer dependent on androgen receptor signaling. As inhibitors of the histone methyltransferase enhancer of zeste homolog 2 (EZH2) are being evaluated clinically for the treatment of advanced prostate cancer, we investigated in this study how EZH2 affects prostate cancer lineage plasticity. Data from genetically engineered mice and human clinical samples demonstrated that genetic or pharmacologic suppression of EZH2 altered chromatin to expand active transcription factor programs. These changes in gene expression during prostate cancer progression increased the diversity of prostate cancer lineage variants that arose. EZH2 suppression did not inhibit disease progression nor therapeutic resistance in this context. These findings advance the current understanding of prostate cancer lineage plasticity and suggest that EZH2 inhibitors may be less effective in treating prostate cancer prone to lineage plasticity. SIGNIFICANCE: EZH2 suppression diversifies prostate cancer lineage plasticity, which has implications for EZH2-targeted therapies that are being evaluated for prostate cancer treatment. See related commentary by Thienger et al., p. 827.

Enhancer of Zeste Homolog 2 Protein↗