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

## TL;DR

This study shows that targeting PRAME or using EZH2 inhibitors can overcome retinoid resistance in skin cancers like basal cell and squamous cell carcinoma.

## Contribution

The study introduces PRAME as a key driver of retinoid resistance in keratinocyte carcinomas and proposes EZH2 inhibition as a novel therapeutic strategy.

## Key findings

- High PRAME expression correlates with reduced epidermal differentiation gene activity in tumors.
- PRAME overexpression impairs retinoid-induced growth suppression and differentiation in keratinocyte carcinomas.
- Combining retinoids with EZH2 inhibitors restores anticancer responses in PRAME-expressing tumors.

## 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.

The study evaluated the function and therapeutic implications of PRAME in basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). The findings demonstrate that PRAME impairs keratinocyte differentiation pathways. Furthermore, PRAME impairs anticancer response to retinoid compounds in BCC and SCC cells. Anticancer response to retinoid treatment was restored by combining retinoid treatment with use of an EZH2 inhibitor.