1. Academic Validation
  2. Enhancer of zeste homolog 2 (EZH2)-dependent sirtuin-3 determines sensitivity to glucose starvation in radioresistant head and neck cancer cells

Enhancer of zeste homolog 2 (EZH2)-dependent sirtuin-3 determines sensitivity to glucose starvation in radioresistant head and neck cancer cells

  • Cell Signal. 2023 Dec 30:115:111029. doi: 10.1016/j.cellsig.2023.111029.
Hyo Won Chang 1 Jung Je Park 2 Won Hyeok Lee 3 Song Hee Kim 3 Jong Cheol Lee 4 Hae Yun Nam 1 Mi Ra Kim 4 Myung Woul Han 3 Yoon Se Lee 5 Sang Yoon Kim 6 Seong Who Kim 7
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
  • 2 Department of Otolaryngology, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju, Republic of Korea.
  • 3 Department of Otolaryngology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea.
  • 4 Department of Otolaryngology, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Republic of Korea.
  • 5 Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
  • 6 Pharosgen Co., Ltd., Seoul, Republic of Korea.
  • 7 Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address: swhokim@gmail.com.
Abstract

Sirtuin 3 (SIRT3) regulates mitochondrial function as a mitochondrial deacetylase during oxidative stress. However, the specific regulatory mechanism and function of SIRT3 in radioresistant Cancer cells are unclear. In this study, we aim to investigate how SIRT3 determines the susceptibility to glucose deprivation and its regulation in p53-based radioresistant head and neck Cancer cells. We observed mitochondrial function using two established isogenic radioresistant subclones (HN3R-A [p53 null] and HN3R-B [p53 R282W]) with intratumoral p53 heterogeneity. Cell counting analysis was performed to evaluate cell proliferation and cell death. The correlation between the regulation of SIRT3 and enhancer of zeste homolog 2 (EZH2) was confirmed by immunoblotting and chromatin immunoprecipitation assay. p53-deficient radioresistant cells (HN3R-A) expression reduced SIRT3 levels and increased sensitivity to glucose deprivation due to mitochondrial dysfunction compared to other cells. In these cells, activation of SIRT3 significantly prevented glucose deprivation-induced cell death, whereas the loss of SIRT3 increased the susceptibility to glucose deficiency. We discovered that radiation-induced EZH2 directly binds to the SIRT3 promoter and represses the expression. Conversely, inhibiting EZH2 increased the expression of SIRT3 through epigenetic changes. Our findings indicate that p53-deficient radioresistant cells with enhanced EZH2 exhibit increased sensitivity to glucose deprivation due to SIRT3 suppression. The regulation of SIRT3 by EZH2 plays a critical role in determining the cell response to glucose deficiency in radioresistant Cancer cells. Therefore, EZH2-dependent SIRT3 could be used as a predictive biomarker to select treatment options for patients with radiation-resistance.

Keywords

EZH2; Glucose starvation; Head and neck cancer cell; Radioresistance; SIRT3.

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