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Overexpression of HDAC9 promotes oral squamous cell carcinoma growth, regulates cell cycle progression, and inhibits apoptosis

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Abstract

Histone deacetylases (HDACs) are a family of deacetylase enzymes that regulate the acetylation state of histones and a variety of other non-histone proteins including key oncogenic and tumor suppressor proteins, which modulates chromatin conformation, leading to regulation of gene expression. HDACs has been grouped into classes I–IV and histone deacetylase 9 (HDAC9) belongs to class IIa which exhibits tissue-specific expression. Recent reports have demonstrated both pro-oncogenic and tumor suppressive role for HDAC9 in different cancers; however, its role in OSCC remains elusive. Here, we investigated the role of HDAC9 in pathogenesis of oral squamous cell carcinoma (OSCC). Our data showed significantly increased mRNA and protein expression of HDAC9 in clinical OSCC samples and UPCI-SCC-116 cells as compared to normal counterpart. Kaplan–Meier analysis showed that the patients with high-level of HDAC9 expression had significantly reduced overall survival than those with low-level of HDAC9 expression (p = 0.034). Knockdown of HDAC9 using siRNA interference suppressed cell proliferation, increased apoptosis, and induced G0/G1 cell cycle arrest in UPCI-SCC-116 cells. Immunofluorescence analysis showed increased nuclear localization of HDAC9 in frozen OSCC sections, and indicative of active HDAC9 that may transcriptionally repress its downstream target genes. Subsequent investigation revealed that overexpression of HDAC9 contributes to OSCC carcinogenesis via targeting a transcription factor, MEF2D, and NR4A1/Nur77, a pro-apoptotic MEF2 target.

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Acknowledgments

Bhawna Rastogi is a PhD student in the Department of Otolaryngology and Head and Neck Surgery, PGIMER, and fellowship was provided by Indian Council of Medical Education and Research, (3/1/3/JRF-2011/HRD 25), New Delhi, India.

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Authors and Affiliations

  1. Department of Otolaryngology and Head and Neck Surgery, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India

    Bhawna Rastogi & Naresh K. Panda

  2. Department of Experimental Medicine and Biotechnology, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India

    Satish K. Raut & Madhu Khullar

  3. Department of Oral Health Sciences Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India

    Vidya Rattan

  4. Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India

    Bishan D. Radotra

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  1. Bhawna Rastogi
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Correspondence to Madhu Khullar.

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Rastogi, B., Raut, S.K., Panda, N.K. et al. Overexpression of HDAC9 promotes oral squamous cell carcinoma growth, regulates cell cycle progression, and inhibits apoptosis. Mol Cell Biochem 415, 183–196 (2016). https://doi.org/10.1007/s11010-016-2690-5

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