Release of transcriptional repression via ErbB2-induced, SUMO-directed phosphorylation of myeloid zinc finger-1 serine 27 activates lysosome redistribution and invasion

Research output: Contribution to journalArticle

Abstract

HER2/ErbB2 activation turns on transcriptional processes that induce local invasion and lead to systemic metastasis. The early transcriptional changes needed for ErbB2-induced invasion are poorly understood. Here, we link ErbB2 activation to invasion via ErbB2-induced, SUMO-directed phosphorylation of a single serine residue, S27, of the transcription factor myeloid zinc finger-1 (MZF1). Utilizing an antibody against MZF1-pS27, we show that the phosphorylation of S27 correlates significantly (p < 0.0001) with high-level expression of ErbB2 in primary invasive breast tumors. Phosphorylation of MZF1-S27 is an early response to ErbB2 activation and results in increased transcriptional activity of MZF1. It is needed for the ErbB2-induced expression of MZF1 target genes CTSB and PRKCA, and invasion of single-cells from ErbB2-expressing breast cancer spheroids. The phosphorylation of MZF1-S27 is preceded by poly-SUMOylation of K23, which can make S27 accessible to efficient phosphorylation by PAK4. Based on our results, we suggest for an activation mechanism where phosphorylation of MZF1-S27 triggers MZF1 dissociation from its transcriptional repressors such as the CCCTC-binding factor (CTCF). Our findings increase understanding of the regulation of invasive signaling in breast cancer by uncovering a detailed biological mechanism of how ErbB2 activation can rapidly lead to its invasion-promoting target gene expression and invasion.

Details

Authors
  • Ditte Marie Brix
  • Siri Amanda Tvingsholm
  • Malene Bredahl Hansen
  • Knut Bundgaard Clemmensen
  • Tiina Ohman
  • Valentina Siino
  • Matteo Lambrughi
  • Klaus Hansen
  • Pietri Puustinen
  • Irina Gromova
  • Peter James
  • Elena Papaleo
  • Markku Varjosalo
  • José Moreira
  • Marja Jäättelä
  • Tuula Kallunki
Organisations
External organisations
  • Danish Cancer Society Research Center
  • University of Helsinki
  • University of Copenhagen
  • Åbo Akademi University
  • University of Turku
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology
  • Medical Genetics
Original languageEnglish
JournalOncogene
Publication statusAccepted/In press - 2019 Jan 8
Publication categoryResearch
Peer-reviewedYes