Androgen Receptor-Independent Function of FoxA1 in Prostate Cancer Metastasis

Jin, Hong; Zhao, Jonathan C.; Ogden, Irene M.; Bergan, Raymond C.; Yu, Jindan

doi:10.1158/0008-5472.can-12-3468

Cited by 119 publications

(148 citation statements)

References 37 publications

(42 reference statements)

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“…15) In prostate cancer cells, FOXA1 binds to the genomic region of SNAI2 and represses its expression. 14) In this study, we showed that FOXA1 induces E-cadherin expression in breast cancer cells. Notably, FOXA1 promoted E-cadherin expression at the mRNA and protein levels in mesenchymal MDA-MB-231 cells, whereas FOXA1 induced E-cadherin expression without affecting its mRNA expression in epithelial MCF7 cells.…”

Section: Discussionmentioning

confidence: 69%

“…Similarly, although FOXA1 is indispensable for androgen receptor-mediated gene expression, FOXA1 suppresses SNAI2 expression independently of androgen receptor in prostate cancer cells. 14) These results suggest that FOXA1 represses gene expression both dependently and independently of estrogen receptors. Recently, we found that FOXA1 suppresses binding of the transcription factor nuclear factor-κB (NF-κB) to the promoter region of interleukin (IL)-6 gene and represses its expression independently of ERα in breast cancer cells.…”

Section: Discussionmentioning

confidence: 90%

“…Because FOXA1 has been reported to suppress Slug expression, 14) we analyzed the involvement of FOXA1 in Slug expression in MCF7 cells. Knockdown of FOXA1 was found to strongly induce Slug expression at the mRNA and protein levels ( Figs.…”

Section: Foxa1 Suppresses Slug Expression In Breast Cancer Cellsmentioning

confidence: 99%

“…11,12) Recent studies have shown that FOXA1 suppresses EMT progression in pancreatic and prostate cancer. 13,14) In breast cancer, FOXA1 is preferentially expressed in estrogen-dependent ERα-positive epithelial breast cancer cells, whereas its expression is lost in estrogen-independent ERα-negative mesenchymal breast cancer cells.15) FOXA1 expression is associated with good prognosis in breast cancer.16) These results suggest that although FOXA1 is crucial for proliferation of estrogen-dependent ERα-positive epithelial breast cancer cells, FOXA1 suppresses conversion from less malignant epithelial cancer to more aggressive mesenchymal cancer. However, the involvement of FOXA1 in EMT progression in breast cancer is not fully understood.…”

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confidence: 99%

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confidence: 99%

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FOXA1 Induces E-Cadherin Expression at the Protein Level <i>via</i> Suppression of Slug in Epithelial Breast Cancer Cells

Anzai

Hirata

Shibazaki

et al. 2017

Biological & Pharmaceutical Bulletin

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Epithelial-to-mesenchymal transition (EMT) is an important process during embryonic development and tumor progression by which adherent epithelial cells acquire mesenchymal properties. Forkhead box protein A1 (FOXA1) is a transcriptional regulator preferentially expressed in epithelial breast cancer cells, and its expression is lost in mesenchymal breast cancer cells. However, the implication of this biased expression of FOXA1 in breast cancer is not fully understood. In this study, we analyzed the involvement of FOXA1 in EMT progression in breast cancer, and found that stable expression of FOXA1 in the mesenchymal breast cancer MDA-MB-231 cells strongly induced the epithelial marker E-cadherin at the mRNA and protein levels. Furthermore, stable expression of FOXA1 was found to reduce the mRNA and protein expression of Slug, a repressor of E-cadherin expression. FOXA1 knockdown in the epithelial breast cancer MCF7 cells reduced E-cadherin protein expression without decreasing its mRNA expression. In addition, FOXA1 knockdown in MCF7 cells up-regulated Slug mRNA and protein expression. Notably, similar to FOXA1 knockdown, stable expression of Slug in MCF7 cells reduced E-cadherin protein expression without decreasing its mRNA expression. Taken together, these results suggest that although FOXA1 can induce E-cadherin mRNA expression, it preferentially promotes E-cadherin expression at the protein level by suppressing Slug expression in epithelial breast cancer, and that the balance of this FOXA1-Slug axis regulates EMT progression.Key words epithelial-mesenchymal transition; E-cadherin; forkhead box protein A1; Slug; estrogen receptor Epithelial-to-mesenchymal transition (EMT) is a process that converts adherent epithelial cells to motile mesenchymal cells during embryonic development. 1) EMT is also involved in tumor progression through inducing metastasis and chemoresistance in tumor cells.2-4) Therefore, a better understanding of the molecular mechanisms underlying EMT in tumor cells is beneficial for development of novel antitumor agents.E-Cadherin is a crucial protein that mediates cell-cell adhesion in epithelial cells.1) E-Cadherin expression is dramatically reduced during EMT, which causes loss of cell-cell adhesion and gain of cell motility. Reduction in E-cadherin expression is mainly caused by the transcriptional repressors of E-cadherin gene (CDH1).2,5) A major transcriptional repressor of CDH1 is the zinc finger factor Slug. Slug binds to the E-box sequences present in the enhancer region of CDH1 and represses its expression. 6)Forkhead box A1 (FOXA1) is a member of the forkhead box family of transcription factors. FOXA1 contains the forkhead DNA-binding domain and the N-and C-terminal transactivation domains.7) FOXA1 regulates expression of many genes involved in the development of various tissues, including mammary gland, liver, midbrain, and lung. 8) FOXA1 is also known to function as a chromatin remodeling factor that opens closed chromatin and facilitates the recruitment of other transcription fa...

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Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 90%

Section: Foxa1 Suppresses Slug Expression In Breast Cancer Cellsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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FOXA1 Induces E-Cadherin Expression at the Protein Level <i>via</i> Suppression of Slug in Epithelial Breast Cancer Cells

Anzai

Hirata

Shibazaki

et al. 2017

Biological & Pharmaceutical Bulletin

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Dynamic expression of SNAI2 in prostate cancer predicts tumor progression and drug sensitivity

et al. 2022

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Prostate cancer is a highly heterogeneous disease, understanding the crosstalk between complex genomic and epigenomic alterations will aid in developing targeted therapeutics. We demonstrate that, even though snail family transcriptional repressor 2 (SNAI2) is frequently amplified in prostate cancer, it is epigenetically silenced in this disease, with dynamic changes in SNAI2 levels showing distinct clinical relevance. Integrative clinical data from 18 prostate cancer cohorts and experimental evidence showed that gene fusion between transmembrane serine protease 2 (TMPRSS2) and ETS transcription factor ERG (ERG) (TMPRSS2–ERG fusion) is involved in the silencing of SNAI2. We created a silencer score to evaluate epigenetic repression of SNAI2, which can be reversed by treatment with DNA methyltransferase inhibitors and histone deacetylase inhibitors. Silencing of SNAI2 facilitated tumor cell proliferation and luminal differentiation. Furthermore, SNAI2 has a major influence on the tumor microenvironment by reactivating tumor stroma and creating an immunosuppressive microenvironment in prostate cancer. Importantly, SNAI2 expression levels in part determine sensitivity to the cancer drugs dasatinib and panobinostat. For the first time, we defined the distinct clinical relevance of SNAI2 expression at different disease stages. We elucidated how epigenetic silencing of SNAI2 controls the dynamic changes of SNAI2 expression that are essential for tumor initiation and progression and discovered that restoring SNAI2 expression by treatment with panobinostat enhances dasatinib sensitivity, indicating a new therapeutic strategy for prostate cancer.

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Down-regulation of TRPS1 stimulates epithelial-mesenchymal transition and metastasis through repression ofFOXA1

et al. 2016

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The tricho-rhino-phalangeal syndrome 1 gene (TRPS1), which was initially found to be associated with tricho-rhino-phalangeal syndrome, is critical for the development and differentiation of bone, hair follicles and kidney. However, its role in cancer progression is largely unknown. In this study, we demonstrated that down-regulation of TRPS1 correlated with distant metastasis, tumour recurrence and poor survival rate in cancer patients. TRPS1 was frequently down-regulated in high-metastatic cancer cell lines from the breast, colon and nasopharynx. Silencing of TRPS1 stimulated epithelial-mesenchymal transition (EMT), migration and invasion in vitro and metastasis in vivo, while TRPS1 over-expression exhibited the opposite effects. Using quantitative proteomics, FOXA1, a negative regulator of epithelial-mesenchymal transition (EMT), was shown to be down-regulated by TRPS1 knockdown. Ectopic expression of FOXA1 blocked the enhancement of EMT, migration and invasion induced by TRPS1 silencing. Mechanistically, TRPS1, acting as a transcription activator, directly induced FOXA1 transcription by binding to the FOXA1 promoter. We further showed that down-regulation of TRPS1 was induced by miR-373 binding to the 3' UTR of TRPS1. Over-expression of TRPS1, but not TRPS1 3' UTR, blocked the enhancement of migration and invasion induced by miR-373. Taken together, we consider that down-regulation of TRPS1 by miR-373, acting as a transcriptional activator, promotes EMT and metastasis by repressing FOXA1 transcription, expanding upon its previously reported role as a transcription repressor. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Androgen Receptor-Independent Function of FoxA1 in Prostate Cancer Metastasis

Cited by 119 publications

References 37 publications

FOXA1 Induces E-Cadherin Expression at the Protein Level <i>via</i> Suppression of Slug in Epithelial Breast Cancer Cells

FOXA1 Induces E-Cadherin Expression at the Protein Level <i>via</i> Suppression of Slug in Epithelial Breast Cancer Cells

Dynamic expression of SNAI2 in prostate cancer predicts tumor progression and drug sensitivity

Down-regulation of TRPS1 stimulates epithelial-mesenchymal transition and metastasis through repression ofFOXA1

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