Supplementary Material - PDF file 1368K, Figure S1. FoxA1 promotes cell cycle progress ion but inhibits cell motility. Figure S2. FoxA1 promotes cell pro liferation through the AR. Figure S3. FoxA1 inhibits PC-3M cell inva sion independently of the AR. Figure S4. WB analysis of Vimentin in FoxA1 knockdown LNCaP cells. Figure S5. FoxA1 directly suppresses SLUG expression. Figure S6. FoxA1 expression is up-regulated in localized PCa, but is significantly down- regulated in metastatic PCa. Figure S7. FoxA1 mutants fail to bind the SLUG enhancer. Table S1. GO analysis of genes repressed by shFoxA1 (i .e. FoxA1-induced genes) in LNCaP cells. Table S2. GO analysis of genes induced by shFoxA1 (i.e. FoxA1-repressed) in LNCaP cells. Table S3. GO analysis of genes repressed by siFoxA1 (i .e. FoxA1-induced genes) in LNCaP cells. Table S4. GO analysis of genes induced by siFoxA1 (i .e. FoxA1-repressed) in LNCaP cells. Table S5. GO analysis of genes repressed by shFoxA1 (i .e. FoxA1-induced genes) in 22RV1 cells. Table S6. GO analysis of genes induced by shFoxA1 (i.e. FoxA1-repressed) 22RV1 cells. Table S7. Sequences of oligonucleotid es used in this study
ARTICLE ABSTRACT
FoxA1 (FOXA1) is a pioneering transcription factor of the androgen receptor (AR) that is indispensible for the lineage-specific gene expression of the prostate. To date, there have been conflicting reports on the role of FoxA1 in prostate cancer progression and prognosis. With recent discoveries of recurrent FoxA1 mutations in human prostate tumors, comprehensive understanding of FoxA1 function has become very important. Here, through genomic analysis, we reveal that FoxA1 regulates two distinct oncogenic processes via disparate mechanisms. FoxA1 induces cell growth requiring the AR pathway. On the other hand, FoxA1 inhibits cell motility and epithelial-to-mesenchymal transition (EMT) through AR-independent mechanism directly opposing the action of AR signaling. Using orthotopic mouse models, we further show that FoxA1 inhibits prostate tumor metastasis in vivo. Concordant with these contradictory effects on tumor progression, FoxA1 expression is slightly upregulated in localized prostate cancer wherein cell proliferation is the main feature, but is remarkably downregulated when the disease progresses to metastatic stage for which cell motility and EMT are essential. Importantly, recently identified FoxA1 mutants have drastically attenuated ability in suppressing cell motility. Taken together, our findings illustrate an AR-independent function of FoxA1 as a metastasis inhibitor and provide a mechanism by which recurrent FoxA1 mutations contribute to prostate cancer progression. Cancer Res; 73(12); 3725–36. ©2013 AACR.
