TWIST1 heterodimerization with e12 requires coordinated protein phosphorylation to regulate periostin expression

Svetlana A. Mikheeva, Nathan D. Camp, Lei Huang, Antrix Jain, Sung Yun Jung, Naze G. Avci, Mari Tokita, Alejandro Wolf-Yadlin, Jing Zhang, Stephen J. Tapscott, Robert C. Rostomily, Andrei M Mikheev

Research output: Contribution to journalArticle

Abstract

Diffuse invasion into adjacent brain matter by glioblastoma (GBM) is largely responsible for their dismal prognosis. Previously, we showed that the TWIST1 (TW) bHLH transcription factor and its regulated gene periostin (POSTN) promote invasive phenotypes of GBM cells. Since TW functional effects are regulated by phosphorylation and dimerization, we investigated how phosphorylation of serine 68 in TW regulates TW dimerization, POSTN expression, and invasion in glioma cells. Compared with wild-type TW, the hypophosphorylation mutant, TW(S68A), impaired TW heterodimerization with the E12 bHLH transcription factor and cell invasion in vitro but had no effect on TW homodimerization. Overexpression of TW:E12 forced dimerization constructs (FDCs) increased glioma cell invasion and upregulated pro-invasive proteins, including POSTN, in concert with cytoskeletal reorganization. By contrast, TW:TW homodimer FDCs inhibited POSTN expression and cell invasion in vitro. Further, phosphorylation of analogous PXSP phosphorylation sites in TW:E12 FDCs (TW S68 and E12 S139) coordinately regulated POSTN and PDGFRa mRNA expression. These results suggested that TW regulates pro-invasive phenotypes in part through coordinated phosphorylation events in TW and E12 that promote heterodimer formation and regulate downstream targets. This new mechanistic understanding provides potential therapeutic strategies to inhibit TW-POSTN signaling in GBM and other cancers.

Original languageEnglish (US)
Article number1392
JournalCancers
Volume11
Issue number9
DOIs
StatePublished - Sep 2019

Keywords

  • Dimerization
  • Glioblastoma
  • Invasion
  • Periostin
  • TWIST1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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