FOXO1A Is a Candidate for the 13q14 Tumor Suppressor Gene Inhibiting Androgen Receptor Signaling in Prostate Cancer

Abstract

Chromosomal deletion is frequent at the region between BRCA2 and RB1 in the q14 band of chromosome 13 (13q14) in human cancers, including prostate cancer, suggesting the presence of a tumor suppressor gene. However, no reasonable candidate has been identified thus far. In this study, we did genetic and functional analyses to identify and evaluate the 13q14 tumor suppressor gene. Hemizygous and homozygous deletions in cell lines/xenografts of prostate cancer mapped the deletion locus to 919 kb, which harbors only one known gene, the FOXO1A transcription factor. Deletion at FOXO1A was detected in 31% to 34% in 6 cell lines, 27 xenografts, and 72 clinical specimens of prostate cancer, and was significantly more frequent than deletions at surrounding loci. In addition, FOXO1A was transcriptionally down-regulated in some prostate cancers. Functionally, ectopic expression of FOXO1A inhibited, and its knockdown promoted, cell proliferation or survival. Furthermore, FOXO1A inhibited androgen-and androgen receptor-mediated gene regulation and cell proliferation. Consistent with the understanding of FOXO1A biology, our findings suggest that FOXO1A is the 13q14 tumor suppressor gene, at least in prostate cancer. As a wellestablished negative effector in the phosphatidylinositol 3-kinase/AKT signaling pathway, FOXO1A inactivation in cancer would impair the therapeutic effect of phosphatidylinositol 3-kinase/AKT inhibitors in cancer treatment. (Cancer Res 2006; 66(14): 6998-7006)

Astrocyte elevated gene-1 is a proliferation promoter in breast cancer via suppressing transcriptional factor FOXO1

“…It has been demonstrated that FOXO proteins could act as tumor suppressors as evidenced by its transcriptional induction of CDK inhibitors, including p21 Cip1 , p27 Kip1 and p57 kip2 (Nakamura et al, 2000;Seoane et al, 2004;Roeb et al, 2007). Indeed, FOXO1 expression is downregulated in prostate cancer and endometrial adenocarcinomas (Dong et al, 2006;Ward et al, 2008). It has been demonstrated that phosphorylation of FOXO (Ser 256 ) by Akt leads to FOXO1 nuclear/ cytoplasmic translocation and subsequent degradation via the ubiquitin-proteasome system (Cardozo and Pagano, 2004;Huang et al, 2005).…”

Cell- and gene-specific regulation of primary target genes by the androgen receptor

“…Of the 20 ARGs that modulate cell proliferation in HPr-1AR, 15 were not reported to be androgen-responsive in LNCaP cells, and two genes (CYR61 and ADAMTS1) that were repressed in HPr-1AR are induced in LNCaP cells (Table 4). Along with AR itself, eight primary ARGs (SNAI2,KRT5,INHBA,IL6,IL6R,ARL4C,F3,and HMGB3) and one ARG (FOXO1A) in HPr-1AR are commonly expressed aberrantly during prostate carcinogenesis (Giri et al 2001;LaTulippe et al 2002;Lapointe et al 2004;Dong et al 2006). Moreover, ARL4C, HMGB3, and AR expression are elevated strikingly in metastatic prostate cancers compared to nonrecurrent primary prostate cancers, whereas expression of F3 is decreased (LaTulippe et al 2002).…”

FOXO-binding partners: it takes two to tango

“…Alternative mechanisms might also be relevant since it was also observed that addition of androgens can lead to proteolysis of FOXO1 by acidic cysteine proteases (Huang et al, 2004). The importance of the FOXO1-AR interaction is strengthened by the observation that expression of FOXO1 in prostate cancer cells is reduced when compared to normal prostates (Dong et al, 2006). Hemizygous deletion of FOXO1A was detected in 31% of primary prostate cancers, while ectopic expression of FOXO1 in two prostate cancer cell lines inhibited their proliferation.…”