Novel cancer stem cell-targeted retinoid ZSH-512 impedes colorectal cancer progress via KDM3A-mediated epigenetic reprogramming

Public summary

*Cancer stem cells (CSCs) play a vital role in tumorigenesis of colorectal cancer (CRC).

*ZSH-512 is a novel synthetic retinoid.

*ZSH-512 exhibits excellent inhibitory effects to CRC CSC in multiple preclinical models.

*ZSH-512 suppresses key stemness-related pathways via RARγ-KDM3A-mediated epigenetic reprogramming.

*ZSH-512 holds promise to provide a novel therapeutic option for patients with advanced CRC.

Abstract

Advanced colorectal cancer (CRC) exhibits weak responses to multiple therapies, primarily due to the presence of cancer stem cells (CSCs), which drive high recurrence rates, metastasis, and drug resistance. We have previously systematically conducted CSC-targeted compound discovery and evaluation studies to inhibit CSC-mediated tumorigenesis and metastasis. Here, we identified ZSH-512, a novel synthetic retinoid that selectively targets retinoic acid receptor (RAR)γ, demonstrating its ability to effectively inhibit CRC-CSCs and patient-derived organoids (PDOs) in vitro and significantly reduce CSC-mediated tumor formation and liver metastasis in mouse models without noticeable toxicity. Mechanistically, integrated analysis of Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq) and RNA sequencing (RNA-seq) revealed that ZSH-512 exerted its effect by modulating the RARγ-KDM3A axis to mediate epigenetic reprogramming and broadly suppress stemness-related signaling pathways, including Wnt, Hippo, and Hedgehog. ZSH-512 efficiently inhibited tumorigenesis in CRC-patient-derived tumor xenografts (PDXs) with high KDM3A expression, suggesting KDM3A as a potential predictive biomarker. Collectively, ZSH-512 is a promising therapeutic candidate for targeting CRC-CSCs with high efficacy.