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Salinomycin inhibits epigenetic modulator EZH2 to enhance death receptors in colon cancer stem cells.
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.
Affiliation
  • Singh AK; Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI) , Lucknow, India.
  • Verma A; Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI) , Lucknow, India.
  • Singh A; Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI) , Lucknow, India.
  • Arya RK; Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI) , Lucknow, India.
  • Maheshwari S; Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI) , Lucknow, India.
  • Chaturvedi P; Academy of Scientific and Innovative Research , New Delhi, India.
  • Nengroo MA; Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI) , Lucknow, India.
  • Saini KK; Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI) , Lucknow, India.
  • Vishwakarma AL; Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI) , Lucknow, India.
  • Singh K; Academy of Scientific and Innovative Research , New Delhi, India.
  • Sarkar J; SAIF, CSIR-CDRI , Lucknow, India.
  • Datta D; Electron Microscopy Unit, CSIR-CDRI , Lucknow, India.
Epigenetics ; 16(2): 144-161, 2021.
Article in En | MEDLINE | ID: mdl-32635858
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pyrans / Neoplastic Stem Cells / Colonic Neoplasms / Receptors, TNF-Related Apoptosis-Inducing Ligand / Enhancer of Zeste Homolog 2 Protein Limits: Humans Language: En Journal: Epigenetics Journal subject: GENETICA Year: 2021 Document type: Article Affiliation country: India Country of publication: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pyrans / Neoplastic Stem Cells / Colonic Neoplasms / Receptors, TNF-Related Apoptosis-Inducing Ligand / Enhancer of Zeste Homolog 2 Protein Limits: Humans Language: En Journal: Epigenetics Journal subject: GENETICA Year: 2021 Document type: Article Affiliation country: India Country of publication: United States