A Novel Target of p53, TCF21, Can Respond to Hypoxia by MAPK Pathway Inactivation in Uterine Corpus Endometrial Carcinoma

DNA Cell Biol. 2018 May;37(5):473-480. doi: 10.1089/dna.2017.4062. Epub 2018 Apr 2.

Abstract

Uterine corpus endometrial carcinoma (UCEC) is a common malignancy in the female reproductive system, associated with high morbidity and mortality. Despite the high prevalence of UCEC, molecular understanding of uterine endothelium tumorigenesis remains poorly understood. In this study, we reported that transcription factor 21 (TCF21) inhibits cancer cell proliferation and invasion following overexpression, in vitro and in vivo. Moreover, in response to hypoxia, TCF21 is highly expressed in UCEC cells carrying wild-type p53, and is transcriptional target of p53. We observed that TCF21 interferes with the MAP kinase pathway, which is supported by a substantially reduced level of phosphorylated mitogen-activated protein kinase 1 (MAPK1 or ERK) in cells expressing a higher level of TCF21. Furthermore, we identified the specific region of TCF21 that is responsible for its interaction with mitogen-activated protein kinase 1 (MEK) and a subsequently reduced activity of ERK. Using molecular docking and mutagenesis analysis, we validated a special domain of TCF21, which can reduce the activity of the MAPK pathway and inhibit uterine endothelium tumor cell growth in vitro. Overall, our study determined that TCF21, a hypoxia-driven p53 target, functions as a tumor suppressor in UCEC and presents as a therapeutic target for tumor treatment.

Keywords: MEK1; TCF21; hypoxia; p53; tumor suppression.

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Cell Line, Tumor
  • Down-Regulation / genetics
  • Endometrial Neoplasms / genetics*
  • Endometrial Neoplasms / pathology
  • Enzyme Activation / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • MAP Kinase Signaling System / genetics*
  • MAP Kinase Signaling System / physiology
  • Mice
  • Mice, Nude
  • Tumor Hypoxia / genetics*
  • Tumor Suppressor Protein p53 / physiology*
  • Uterine Neoplasms / genetics*
  • Uterine Neoplasms / pathology

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • TCF21 protein, human
  • TP53 protein, human
  • Tumor Suppressor Protein p53