A Positive Feedback Loop between c-Myc Upregulation, Glycolytic Shift, and Histone Acetylation Enhances Cancer Stem Cell-like Property and Tumorigenicity of Cr(VI)-transformed Cells

Marco Clementino, Jie Xie, Ping Yang, Yunfei Li, Hsuan Pei Lin, William K. Fenske, Hua Tao, Kazuya Kondo, Chengfeng Yang, Zhishan Wang

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Chronic hexavalent chromium [Cr(VI)] exposure causes lung cancer and other types of cancer; however, the mechanism of Cr(VI) carcinogenesis remains to be clearly defined. Our recent study showed that chronic Cr(VI) exposure upregulates the proto oncogene c-Myc expression, which contributes significantly to Cr(VI)-induced cell transformation, cancer stem cell (CSC)-like property and tumorigenesis. c-Myc is a master regulator of cancer cell abnormal metabolism and accumulating evidence suggests that metabolism dysregulation plays an important role in both cancer development and progression. However, little is known about the role of metabolism dysregulation in Cr(VI) carcinogenesis. This study was performed to investigate the potential role and mechanism of metabolism dysregulation in Cr(VI) carcinogenesis. It was found that Cr(VI)-transformed cells display glycolytic shift, which depends on the upregulation of c-Myc. The glycolytic shift in Cr(VI)transformed cells led to increased production of acetyl coenzyme A (acetyl-CoA) and elevation of histone acetylation. This, in turn, upregulated the expression of an acetyl-CoA producing key enzyme ATP citrate lyase and c-Myc, forming a positive feedback loop between the upregulation of c-Myc expression, glycolytic shift and increased histone acetylation. It was further determined that glucose depletion not only reverses the glycolytic shift in Cr(VI)-transformed cells, but also significantly reduces their growth, CSC-like property and tumorigenicity. These findings indicate that glycolytic shift plays an important role in maintaining malignant phenotypes of Cr(VI)-transformed cells, suggesting that metabolism dysregulation is critically involved in Cr(VI) carcinogenesis.

Original languageEnglish
Pages (from-to)71-83
Number of pages13
JournalToxicological Sciences
Volume177
Issue number1
DOIs
StatePublished - Sep 1 2020

Bibliographical note

Funding Information:
National Institutes of Health/National Institute of Environmental Health Sciences (R01ES029496, R01ES026151, R01ES029942, P30ES026529); the University of Kentucky Center for Appalachian Research in Environmental Sciences Career Development Award. This research was also supported by the Shared Resources Facilities on Redox Metabolism and Biospecimen Procurement and Translational Pathology at University of Kentucky Markey Cancer Center (P30CA177558).

Publisher Copyright:
© The Author(s) 2020. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.

Keywords

  • ATP citrate lyase
  • Acetyl-CoA
  • C-Myc
  • Cancer stem cell-like property
  • Carcinogenesis
  • Glycolytic shift
  • Hexavalent chromium

ASJC Scopus subject areas

  • Toxicology

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