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

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.