title: FOXO1 inhibits Runx2 transcriptional activity and prostate cancer cell migration and invasion.
abstract: Prostate cancer patients with regional lymph node involvement at radical prostatectomy often experience disease progression to other organs, with the bone as the predominant site. The transcription factor Runx2 plays an important role in bone formation and prostate cancer cell migration, invasion, and metastasis. Here we showed that the forkhead box O (FOXO1) protein, a key downstream effector of the tumor suppressor PTEN, inhibits the transcriptional activity of Runx2 in prostate cancer cells. This inhibition was enhanced by PTEN but diminished by active Akt. FOXO1 bound to Runx2 in vitro and in vivo and suppressed Runx2's activity independent of its transcriptional function. FOXO1 inhibited Runx2-promoted migration of prostate cancer cells, whereas silencing of endogenous FOXO1 enhanced prostate cancer cell migration in a Runx2-dependent manner. Forced expression of FOXO1 also inhibited Runx2-promoted prostate cancer cell invasion. Finally, we found that expression of PTEN and the level of FOXO1 in the nucleus is inversely correlated with expression of Runx2 in a cohort of prostate cancer specimens from patients with lymph node and bone metastasis. These data reveal FOXO1 as a critical negative regulator of Runx2 in prostate cancer cells. Inactivation of FOXO1 due to frequent loss of PTEN in prostate cancer cells may leave the oncogenic activities of Runx2 unchecked, thereby driving promiscuous expression of Runx2 target genes involved in cell migration and invasion and favoring prostate cancer progression.
authors.affiliation: Department of Laboratory Medicine, University of Minnesota, MN, USA.
authors.forename: Haijun
authors.initials: H
authors.lastname: Zhang
authors.forename: Yunqian
authors.initials: Y
authors.lastname: Pan
authors.forename: Li
authors.initials: L
authors.lastname: Zheng
authors.forename: Chungyoul
authors.initials: C
authors.lastname: Choe
authors.forename: Bruce
authors.initials: B
authors.lastname: Lindgren
authors.forename: Eric D
authors.initials: ED
authors.lastname: Jensen
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Westendorf
authors.forename: Liang
authors.initials: L
authors.lastname: Cheng
authors.forename: Haojie
authors.initials: H
authors.lastname: Huang
mesh_terms: D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D009361:Neoplasm Invasiveness; D051058:Oncogene Protein v-akt / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C493709:RUNX2 protein, human; D051058:Oncogene Protein v-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human