KAT5 promotes invasion and metastasis through C-MYC stabilization in ATC

Xi Wei, Shang Cai, Rebecca J. Boohaker, Joshua Fried, Ying Li, Linfei Hu, Yi Pan, Ruifen Cheng, Sheng Zhang, Ye Tian, Ming Gao, Bo Xu

Research output: Contribution to journalArticle

Abstract

Anaplastic thyroid cancer (ATC) is an aggressive cancer with poor clinical prognosis. However, mechanisms driving ATC aggressiveness is not well known. Components of the DNA damage response (DDR) are frequently found mutated or aberrantly expressed in ATC. The goal of this study is to establish the functional link between histone acetyltransferase lysine (K) acetyltransferase 5 (KAT5, a critical DDR protein) and ATC invasiveness using clinical, in vitro and in vivo models. We analyzed the expression of KAT5 by immunohistochemistry and assessed its relationship with metastasis and overall survival in 82 ATC patients. Using cellular models, we established functional connection of KAT5 expression and C-MYC stabilization. We then studied the impact of genetically modified KAT5 expression on ATC metastasis in nude mice. In clinical samples, there is a strong correlation of KAT5 expression with ATC metastasis (P = 0.0009) and overall survival (P = 0.0017). At the cellular level, upregulation of KAT5 significantly promotes thyroid cancer cell proliferation and invasion. We also find that KAT5 enhances the C-MYC protein level by inhibiting ubiquitin-mediated degradation. Further evidence reveals that KAT5 acetylates and stabilizes C-MYC. Finally, we prove that altered KAT5 expression influences ATC lung metastases in vivo. KAT5 promotes ATC invasion and metastases through stabilization of C-MYC, demonstrating it as a new biomarker and therapeutic target for ATC.

LanguageEnglish (US)
Pages141-151
Number of pages11
JournalEndocrine-related cancer
Volume26
Issue number1
DOIs
StatePublished - Jan 1 2019

Fingerprint

Neoplasm Metastasis
DNA Damage
Anaplastic Thyroid Carcinoma
Histone Acetyltransferases
Survival
Ubiquitin
Protein C
Thyroid Neoplasms
Nude Mice
Lung Neoplasms
Up-Regulation
Biomarkers
Immunohistochemistry
Cell Proliferation
Neoplasms
Proteins

Keywords

  • anaplastic thyroid cancer
  • C-MYC
  • invasion
  • KAT5
  • metastasis

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Oncology
  • Endocrinology
  • Cancer Research

Cite this

Wei, X., Cai, S., Boohaker, R. J., Fried, J., Li, Y., Hu, L., ... Xu, B. (2019). KAT5 promotes invasion and metastasis through C-MYC stabilization in ATC. Endocrine-related cancer, 26(1), 141-151. https://doi.org/10.1530/ERC-18-0193

KAT5 promotes invasion and metastasis through C-MYC stabilization in ATC. / Wei, Xi; Cai, Shang; Boohaker, Rebecca J.; Fried, Joshua; Li, Ying; Hu, Linfei; Pan, Yi; Cheng, Ruifen; Zhang, Sheng; Tian, Ye; Gao, Ming; Xu, Bo.

In: Endocrine-related cancer, Vol. 26, No. 1, 01.01.2019, p. 141-151.

Research output: Contribution to journalArticle

Wei, X, Cai, S, Boohaker, RJ, Fried, J, Li, Y, Hu, L, Pan, Y, Cheng, R, Zhang, S, Tian, Y, Gao, M & Xu, B 2019, 'KAT5 promotes invasion and metastasis through C-MYC stabilization in ATC' Endocrine-related cancer, vol. 26, no. 1, pp. 141-151. https://doi.org/10.1530/ERC-18-0193
Wei, Xi ; Cai, Shang ; Boohaker, Rebecca J. ; Fried, Joshua ; Li, Ying ; Hu, Linfei ; Pan, Yi ; Cheng, Ruifen ; Zhang, Sheng ; Tian, Ye ; Gao, Ming ; Xu, Bo. / KAT5 promotes invasion and metastasis through C-MYC stabilization in ATC. In: Endocrine-related cancer. 2019 ; Vol. 26, No. 1. pp. 141-151.
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