ATDC mediates a TP63-regulated basal cancer invasive program

Oncogene. 2019 May;38(18):3340-3354. doi: 10.1038/s41388-018-0646-9. Epub 2019 Jan 14.

Abstract

Basal subtype cancers are deadly malignancies but the molecular events driving tumor lethality are not completely understood. Ataxia-telangiectasia group D complementing gene (ATDC, also known as TRIM29), is highly expressed and drives tumor formation and invasion in human bladder cancers but the factor(s) regulating its expression in bladder cancer are unknown. Molecular subtyping of bladder cancer has identified an aggressive basal subtype, which shares molecular features of basal/squamous tumors arising in other organs and is defined by activation of a TP63-driven gene program. Here, we demonstrate that ATDC is linked with expression of TP63 and highly expressed in basal bladder cancers. We find that TP63 binds to transcriptional regulatory regions of ATDC and KRT14 directly, increasing their expression, and that ATDC and KRT14 execute a TP63-driven invasive program. In vivo, ATDC is required for TP63-induced bladder tumor invasion and metastasis. These results link TP63 and the basal gene expression program to ATDC and to aggressive tumor behavior. Defining ATDC as a molecular determinant of aggressive, basal cancers may lead to improved biomarkers and therapeutic approaches.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Line, Tumor
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation, Neoplastic / physiology
  • Humans
  • Neoplasm Invasiveness / pathology*
  • Neoplasms, Basal Cell / metabolism
  • Neoplasms, Basal Cell / pathology
  • Neoplasms, Squamous Cell / metabolism
  • Neoplasms, Squamous Cell / pathology
  • Transcription Factors / metabolism*
  • Transcription, Genetic / physiology
  • Tumor Suppressor Proteins / metabolism*
  • Urinary Bladder Neoplasms / metabolism*
  • Urinary Bladder Neoplasms / pathology*

Substances

  • DNA-Binding Proteins
  • TP63 protein, human
  • TRIM29 protein, human
  • Transcription Factors
  • Tumor Suppressor Proteins