title: Prolyl isomerase Pin1 downregulates tumor suppressor RUNX3 in breast cancer.
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.
authors.affiliation: Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors.forename: Y-H
authors.initials: YH
authors.lastname: Nicole Tsang
authors.forename: X-W
authors.initials: XW
authors.lastname: Wu
authors.forename: J-S
authors.initials: JS
authors.lastname: Lim
authors.forename: C
authors.initials: C
authors.lastname: Wee Ong
authors.forename: M
authors.initials: M
authors.lastname: Salto-Tellez
authors.forename: K
authors.initials: K
authors.lastname: Ito
authors.forename: Y
authors.initials: Y
authors.lastname: Ito
authors.forename: L-F
authors.initials: LF
authors.lastname: Chen
mesh_terms: D020816:Amino Acid Motifs; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D050677:Core Binding Factor Alpha 3 Subunit / Q000032:analysis / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D015536:Down-Regulation; D005260:Female; D006801:Humans; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000032:analysis / Q000502:physiology*; D010766:Phosphorylation; D055550:Protein Stability; D025521:Tumor Suppressor Proteins; D054875:Ubiquitination
chemical_list: D050677:Core Binding Factor Alpha 3 Subunit; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; C493729:Runx3 protein, human; D025521:Tumor Suppressor Proteins; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse