Prolyl isomerase Pin1 downregulates tumor suppressor RUNX3 in breast cancer

Y-H Nicole Tsang, X-W Wu, J-S Lim, C Wee Ong, M Salto-Tellez, K Ito, Y Ito, L-F Chen

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)

Abstract

Emerging evidence demonstrates that RUNX3 is a tumor suppressor in breast cancer. Inactivation of RUNX3 in mice results in spontaneous mammary gland tumors, and decreased or silenced expression of RUNX3 is frequently found in breast cancer cell lines and human breast cancer samples. However, the underlying mechanism for initiating RUNX3 inactivation in breast cancer remains elusive. Here, we identify prolyl isomerase Pin1, which is often overexpressed in breast cancer, as a key regulator of RUNX3 inactivation. In human breast cancer cell lines and breast cancer samples, expression of Pin1 inversely correlates with the expression of RUNX3. In addition, Pin1 recognizes four phosphorylated Ser/Thr-Pro motifs in RUNX3 via its WW domain. Binding of Pin1 to RUNX3 suppresses the transcriptional activity of RUNX3. Furthermore, Pin1 reduces the cellular levels of RUNX3 in an isomerase activity-dependent manner by inducing the ubiquitination and proteasomal degradation of RUNX3. Knocking down Pin1 enhances the cellular levels and transcriptional activity of RUNX3 by inhibiting the ubiquitination and degradation of RUNX3. Our results identify Pin1 as a new regulator of RUNX3 inactivation in breast cancer.
Original languageEnglish
Pages (from-to)1488-1496
JournalOncogene
Volume32
Issue number12
Early online date14 May 2012
DOIs
Publication statusPublished - 21 Mar 2013

Keywords

  • Phosphorylation
  • Down-Regulation
  • Amino Acid Motifs
  • Protein Stability
  • Humans
  • Ubiquitination
  • Core Binding Factor Alpha 3 Subunit
  • Breast Neoplasms
  • Peptidylprolyl Isomerase
  • Cell Line, Tumor
  • Female
  • Tumor Suppressor Proteins

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