1. ZSCAN4 facilitates chromatin remodeling and promotes the cancer stem cell phenotype.
- Author
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Portney BA, Arad M, Gupta A, Brown RA, Khatri R, Lin PN, Hebert AM, Angster KH, Silipino LE, Meltzer WA, Taylor RJ, and Zalzman M
- Subjects
- Acetylation, Animals, Carcinoma, Squamous Cell metabolism, Carcinoma, Squamous Cell therapy, Cell Line, Tumor, DNA-Binding Proteins metabolism, Head and Neck Neoplasms metabolism, Head and Neck Neoplasms therapy, Histones metabolism, Humans, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Nanog Homeobox Protein genetics, Nanog Homeobox Protein metabolism, Octamer Transcription Factor-3 genetics, Octamer Transcription Factor-3 metabolism, Phenotype, RNA Interference, Transcription Factors metabolism, Xenograft Model Antitumor Assays methods, Carcinoma, Squamous Cell genetics, Chromatin Assembly and Disassembly genetics, DNA-Binding Proteins genetics, Gene Expression Regulation, Neoplastic, Head and Neck Neoplasms genetics, Neoplastic Stem Cells metabolism, Transcription Factors genetics
- Abstract
Cancer stem cells (CSCs) are cells within tumors that maintain the ability to self-renew, drive tumor growth, and contribute to therapeutic resistance and cancer recurrence. In this study, we investigate the role of Zinc finger and SCAN domain containing 4 (ZSCAN4) in human head and neck squamous cell carcinoma (HNSCC). The murine Zscan4 is involved in telomere maintenance and genomic stability of mouse embryonic stem cells. Our data indicate that the human ZSCAN4 is enriched for, marks and is co-expressed with CSC markers in HNSCC. We show that transient ZSCAN4 induction for just 2 days increases CSC frequency both in vitro and in vivo and leads to upregulation of pluripotency and CSC factors. Importantly, we define for the first time the role of ZSCAN4 in altering the epigenetic profile and regulating the chromatin state. Our data show that ZSCAN4 leads to a functional histone 3 hyperacetylation at the promoters of OCT3/4 and NANOG, leading to an upregulation of CSC factors. Consistently, ZSCAN4 depletion leads to downregulation of CSC markers, decreased ability to form tumorspheres and severely affects tumor growth. Our study suggests that ZSCAN4 plays an important role in the maintenance of the CSC phenotype, indicating it is a potential therapeutic target in HNSCC.
- Published
- 2020
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