Salinomycin inhibits epigenetic modulator EZH2 to enhance death receptors in colon cancer stem cells. Issue 2 (1st February 2021)

• Record Type: Journal Article
• Authors: Singh, Anup Kumar; Verma, Ayushi; Singh, Akhilesh; Arya, Rakesh Kumar; Maheshwari, Shrankhla; Chaturvedi, Priyank; Nengroo, Mushtaq Ahmad; Saini, Krishan Kumar; Vishwakarma, Achchhe Lal; Singh, Kavita; Sarkar, Jayanta; Datta, Dipak
• Is Part Of: Epigenetics. Volume 16:Issue 2(2021)
• Page Start: 144
• Page End: 161
• Publication Date: 2021-02-01
• Subjects: EZH2 -- cancer stem cells -- death receptors -- salinomycin -- apoptosis; Epigenesis -- Periodicals; Epigenetica; 572.86505
• DOI: 10.1080/15592294.2020.1789270
• Languages: English
• ISSNs: 1559-2294

Abstract

ABSTRACT: Drug resistance is one of the trademark features of Cancer Stem Cells (CSCs). We and others have recently shown that paucity of functional death receptors (DR4/5) on the cell surface of tumour cells is one of the major reasons for drug resistance, but their involvement in the context of in CSCs is poorly understood. By harnessing CSC specific cytotoxic function of salinomycin, we discovered a critical role of epigenetic modulator EZH2 in regulating the expression of DRs in colon CSCs. Our unbiased proteome profiler array approach followed by ChIP analysis of salinomycin treated cells indicated that the expression of DRs, especially DR4 is epigenetically repressed in colon CSCs. Concurrently, EZH2 knockdown demonstrated increased expression of DR4/DR5, significant reduction of CSC phenotypes such as spheroid formation in-vitro and tumorigenic potential in-vivo in colon cancer. TCGA data analysis of human colon cancer clinical samples shows strong inverse correlation between EZH2 and DR4. Taken together, this study provides an insight about epigenetic regulation of DR4 in colon CSCs and advocates that drug-resistant colon cancer can be therapeutically targeted by combining TRAIL and small molecule EZH2 inhibitors.