RUNX2 expression in thyroid and breast cancer requires the cooperation of three non-redundant enhancers under the control of BRD4 and c-JUN

Valentina Sancisi, Gloria Manzotti, Mila Gugnoni, Teresa Rossi, Greta Gandolfi, Giulia Gobbi, Federica Torricelli, Francesca Catellani, Italo Faria do Valle, Daniel Remondini, Gastone Castellani, Moira Ragazzi, Simonetta Piana, Alessia Ciarrocchi

Research output: Contribution to journalArticle

Abstract

Aberrant reactivation of embryonic pathways is a common feature of cancer. RUNX2 is a transcription factor crucial during embryogenesis that is aberrantly reactivated in many tumors, including thyroid and breast cancer, where it promotes aggressiveness and metastatic spreading. Currently, the mechanisms driving RUNX2 expression in cancer are still largely unknown. Here we showed that RUNX2 transcription in thyroid and breast cancer requires the cooperation of three distantly located enhancers (ENHs) brought together by chromatin three-dimensional looping. We showed that BRD4 controls RUNX2 by binding to the newly identified ENHs and we demonstrated that the anti-proliferative effects of bromodomain inhibitors (BETi) is associated with RUNX2 transcriptional repression. We demonstrated that each RUNX2 ENH is potentially controlled by a distinct set of TFs and we identified c-JUN as the principal pivot of this regulatory platform. We also observed that accumulation of genetic mutations within these elements correlates with metastatic behavior in human thyroid tumors. Finally, we identified RAINs, a novel family of ENH-associated long non-coding RNAs, transcribed from the identified RUNX2 regulatory unit. Our data provide a new model to explain how RUNX2 expression is reactivated in thyroid and breast cancer and how cancer-driving signaling pathways converge on the regulation of this gene.

Original languageEnglish
Pages (from-to)11249-11267
Number of pages19
JournalNucleic Acids Research
Volume45
Issue number19
DOIs
Publication statusPublished - Nov 2 2017

Keywords

  • Blotting, Western
  • Breast Neoplasms
  • Cell Line, Tumor
  • Core Binding Factor Alpha 1 Subunit
  • Enhancer Elements, Genetic
  • Gene Expression Regulation, Neoplastic
  • Humans
  • MCF-7 Cells
  • Nuclear Proteins
  • Protein Binding
  • Proto-Oncogene Proteins c-jun
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Thyroid Neoplasms
  • Transcription Factors
  • Journal Article

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