Down-regulation of Forkhead box protein A1 (FOXA1) leads to cancer stem cell-like properties in tamoxifen-resistant breast cancer cells through induction of interleukin-6

Yamaguchi, Noritaka; Nakayama, Yuji; Yamaguchi, Naoto

doi:10.1074/jbc.m116.763276

Cited by 58 publications

(44 citation statements)

References 34 publications

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“…17) Whole cell lysates prepared in sodium dodecyl sulfate (SDS) sample buffer were subjected to SDS-polyacrylamide gel electrophoresis and electrotransferred onto polyvinylidene difluoride membranes. Protein bands were detected with appropriate antibodies and analyzed using a ChemiDoc XRS+ image analyzer (Bio-Rad, Richmond, CA, U.S.A.).…”

Section: Methodsmentioning

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: Methodsmentioning

confidence: 99%

“…17) cDNA encoding Slug was generated by PCR from the reverse-transcribed product of MDA-MB-231 total RNA and was subcloned into the pIRESpuro3 vector (TaKaRa, Shiga, Japan). A myc tag was added to the N-terminal cDNA of Slug.…”

Section: Methodsmentioning

confidence: 99%

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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“…Previous studies have proven that FOX proteins are strongly associated with CSCs. For example, downregulation of FOXA1 expression promotes CSC-like properties in breast cancer cells, leading to tamoxifen resistance [ 14 ]. FOXM1 increases the CSC population and induces endocrine resistance in breast cancer [ 15 ], and FOXQ1 inhibition with diallyl disulfide is a novel strategy for suppressing breast CSCs [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

FOXC1 induces cancer stem cell-like properties through upregulation of beta-catenin in NSCLC

Cao

Wang

Gao

et al. 2018

J Exp Clin Cancer Res

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BackgroundAccumulating evidence suggests that cancer stem cells (CSCs) play a critical role in tumor initiation, progression and therapy, and recent studies have indicated that Forkhead box C1 (FOXC1) is strongly associated with CSCs. This study investigates the regulatory effects of FOXC1 on CSC-like properties in non-small cell lung cancer (NSCLC).MethodsWe analyzed FOXC1 expression in NSCLC using the Cancer Genome Atlas (TCGA) database on UALCANC and performed survival analyses of NSCLC patients on Human Protein Atlas. CSC-like properties were analyzed based on CSC marker-positive cell population, self-renewal ability, stemness-related gene expression, tumorigenicity and drug resistance. The percentage of CD133+ cells was analyzed by flow cytometric analysis. Self-renewal ability was detected by sphere-formation analysis. Real-time PCR, western blotting and immunohistochemical staining were employed to detect mRNA and protein levels. Tumorigenicity was determined based on a xenograft formation assay, and effects of FOXC1 on drug resistance were assessed by cell viability and apoptosis assays. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays were used to investigate the binding of FOXC1 to beta-catenin promoter.ResultsFOXC1 expression was found to be elevated in NSCLC tissues and negatively correlated with patient survival. FOXC1 knockdown reduced CD133+ cell percentage, suppressed self-renewal ability, decreased expression of stemness-related genes (Oct4, NANOG, SOX2 and ABCG2) and inhibited NSCLC cell tumorigenicity in vivo. Moreover, FOXC1 knockdown increased cisplatin and docetaxel sensitivity and reduced gefitinib resistance, whereas FOXC1 overexpression enhanced CSC-like properties. Luciferase reporter and ChIP assays showed beta-catenin to be a direct transcriptional target of FOXC1. Furthermore, overexpression of beta-catenin reversed the CSC-like property inhibition induced by FOXC1 knockdown, and knockdown of beta-catenin attenuated the CSC-like properties induced by FOXC1 overexpression.ConclusionsThis study demonstrates that FOXC1 induces CSC-like properties in NSCLC by promoting beta-catenin expression. The findings indicate that FOXC1 is a potential molecular target for anti-CSC-based therapies in NSCLC.

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“…Western blot analysis was performed using an enhanced chemiluminescence kit (Merck Millipore) as described previously . The intensity of chemiluminescence was measured using Quantity One software (Bio‐Rad, Richmond, CA).…”

Section: Methodsmentioning

confidence: 99%

“…Complementary DNA (cDNA) encoding human FOXA1 was subcloned into the pIRESpuro3-CAG vector as described previously. 16 Human Smad3 cDNA subcloned into the pCMV_S-Flag vector was obtained from RIKEN BRC (RDB07019). cDNAs encoding Smad4 (a Strep tag was added to the N-terminus) and importin7 (a myc tag was added to the N-terminus) were generated by polymerase chain reaction (PCR) from the reverse-transcribed product of MCF7 total RNA and subcloned into the pIRESpuro3-CAG vector.…”

Section: Plasmidsmentioning

confidence: 99%

Forkhead box protein A1 confers resistance to transforming growth factor‐β‐induced apoptosis in breast cancer cells through inhibition of Smad3 nuclear translocation

Hirata

Takakura

Shibazaki

et al. 2018

J of Cellular Biochemistry

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Transforming growth factor-β (TGF-β) induces apoptosis of normal epithelial cells, such as mammary epithelium. Although breast cancer progression associates with acquisition of resistance to TGF-β-induced apoptosis, the molecular mechanisms underlying this resistance are largely unknown. Here, we show that forkhead box protein A1 (FOXA1), which is known as a pioneer transcription factor, suppresses TGF-β-induced apoptosis of estrogen receptor-positive breast cancer cells. FOXA1 is found to inhibit nuclear translocation of Smad3, a key transcription factor downstream of TGF-β signaling, through suppression of the binding of Smad3 to the nuclear import receptor importin7. Furthermore, RNA sequencing analyses show that knockdown of FOXA1 upregulates Smad3-mediated proapoptotic gene expression. These results demonstrate that FOXA1 as a potent survival factor that suppresses TGF-β-induced apoptosis by inhibiting Smad3 signaling in estrogen receptor-positive breast cancer cells. Thus, we provide evidence for the first time that FOXA1 localizing to the cytoplasm negatively regulates Smad3-induced apoptosis in TGF-β-mediated signal transduction.

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Down-regulation of Forkhead box protein A1 (FOXA1) leads to cancer stem cell-like properties in tamoxifen-resistant breast cancer cells through induction of interleukin-6

Cited by 58 publications

References 34 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

FOXC1 induces cancer stem cell-like properties through upregulation of beta-catenin in NSCLC

Forkhead box protein A1 confers resistance to transforming growth factor‐β‐induced apoptosis in breast cancer cells through inhibition of Smad3 nuclear translocation

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