KLF4 suppresses estrogen-dependent breast cancer growth by inhibiting the transcriptional activity of ERα

Akaogi, Kensuke; Nakajima, Yuka; Ito, Ichiaki; Kawasaki, Shohei; Oie, Shohei; Murayama, Akiko; Kimura, Kazuhiro; Yanagisawa, Junn

doi:10.1038/onc.2009.151

Cited by 100 publications

(79 citation statements)

References 46 publications

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“…KLF4 can function as either an inductive or inhibitory transcription factor acting upon, for example, various cell cycle regulatory genes or differentiation genes, including CDH1 (9,10,27,38). Loss of KLF4 in various cancers, including colon, breast, and gastric cancers, is consistent with tumor-suppressive functions (3,28,35). Ectopic overexpression of KLF4 inhibits growth and invasiveness of tumor cell lines, including prostate cancer (12,33,35,39).…”

Section: Discussionmentioning

confidence: 97%

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Critical and Reciprocal Regulation of KLF4 and SLUG in Transforming Growth Factor β-Initiated Prostate Cancer Epithelial-Mesenchymal Transition

Liu

Abou-Kheir

Yin

et al. 2012

Molecular and Cellular Biology

142

117

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Epithelial-mesenchymal transition (EMT) is implicated in various pathological processes within the prostate, including benign prostate hyperplasia (BPH) and prostate cancer progression. However, an ordered sequence of signaling events initiating carcinoma-associated EMT has not been established. In a model of transforming growth factor ␤ (TGF␤)-induced prostatic EMT, SLUG is the dominant regulator of EMT initiation in vitro and in vivo, as demonstrated by the inhibition of EMT following Slug depletion. In contrast, SNAIL depletion was significantly less rate limiting. TGF␤-stimulated KLF4 degradation is required for SLUG induction. Expression of a degradation-resistant KLF4 mutant inhibited EMT, and furthermore, depletion of Klf4 was sufficient to initiate SLUG-dependent EMT. We show that KLF4 and another epithelial determinant, FOXA1, are direct transcriptional inhibitors of SLUG expression in mouse and human prostate cancer cells. Furthermore, self-reinforcing regulatory loops for SLUG-KLF4 and SLUG-FOXA1 lead to SLUG-dependent binding of polycomb repressive complexes to the Klf4 and Foxa1 promoters, silencing transcription and consolidating mesenchymal commitment. Analysis of tissue arrays demonstrated decreased KLF4 and increased SLUG expression in advanced-stage primary prostate cancer, substantiating the involvement of the EMT signaling events described in model systems.

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Section: Discussionmentioning

confidence: 97%

“…The expression of KLF4, an epithelium-determining transcription factor, decreases with progression in various epithelial cancers, including prostate cancer (3,28,33,35). Therefore, we investigated the relationship of SLUG, KLF4, and FOXA1, another epithelial transcription factor important for prostate function (15,22).…”

mentioning

confidence: 99%

Critical and Reciprocal Regulation of KLF4 and SLUG in Transforming Growth Factor β-Initiated Prostate Cancer Epithelial-Mesenchymal Transition

Liu

Abou-Kheir

Yin

et al. 2012

Molecular and Cellular Biology

142

117

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“…In contrast, Akaogi et al reported that a review of nine independent, publicly available gene expression data sets revealed decreased KLF4 mRNA expression in breast cancers when compared with normal breast. In addition, KLF4 was inversely correlated with increasing tumor grade in 15 independent gene expression array analyses of breast cancer samples (17). Expression of KLF4 protein is also relatively low in breast cancer cell lines compared with non-transformed mammary epithelial cells (18).…”

Section: Krüppel-like Factor 4 (Klf4)mentioning

confidence: 95%

Krüppel-like Factor 4 Inhibits Epithelial-to-Mesenchymal Transition through Regulation of E-cadherin Gene Expression

Yori

Johnson

Zhou

et al. 2010

Journal of Biological Chemistry

149

167

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The Krüppel-like factor 4 (KLF4) is a transcriptional regulator of proliferation and differentiation in epithelial cells, both during development and tumorigenesis. Although KLF4 functions as a tumor suppressor in several tissues, including the colon, the role of KLF4 in breast cancer is less clear. Here, we show that KLF4 is necessary for maintenance of the epithelial phenotype in non-transformed MCF-10A mammary epithelial cells. KLF4 silencing led to alterations in epithelial cell morphology and migration, indicative of an epithelial-to-mesenchymal transition. Consistent with these changes, decreased levels of KLF4 also resulted in the loss of E-cadherin protein and mRNA. Promoter/reporter analyses revealed decreased E-cadherin promoter activity with KLF4 silencing, while chromatin immunoprecipitation identified endogenous KLF4 binding to the GC-rich/E-box region of this promoter. Furthermore, forced expression of KLF4 in the highly metastatic MDA-MB-231 breast tumor cell line was sufficient to restore E-cadherin expression and suppress migration and invasion. These findings identify E-cadherin as a novel transcriptional target of KLF4. The clear requirement for KLF4 to maintain E-cadherin expression and prevent epithelial-to-mesenchymal transition in mammary epithelial cells supports a metastasis suppressive role for KLF4 in breast cancer.Krüppel-like factor 4 (KLF4) 3 is a zinc finger transcription factor that was first identified in a screen for transcription factors involved in growth regulation (1). KLF4 is primarily regarded as a negative regulator of the cell cycle, repressing a multitude of genes that promote proliferation while at the same time up-regulating inhibitors of proliferation (2). KLF4 also plays a crucial role in differentiation during organogenesis of various tissues such as the skin, colon, and eye (3-5). With the advent of induced pluripotent stem cells, KLF4 has gained recognition as one of the "pluripotency genes" that can reprogram somatic cells into a stem cell-like state (6), acting in the capacity to maintain self-renewal (7).Given its stem cell-promoting activity and its ability to regulate growth and differentiation during development, it is not surprising that KLF4 also plays various roles in tumorigenesis. The frequent loss of KLF4 expression in gastric and colorectal cancers has led to studies revealing a tumor-suppressive role for this factor in these and other tissues (8 -13). Conversely, overexpression of KLF4 in the skin leads to squamous cell carcinoma (14). However, the role of KLF4 during the progression of breast cancer is not well defined. Immunohistochemical studies have revealed that KLF4 expression can be increased and undergo altered localization in DCIS of the breast (15), suggesting that it may act as an oncogene in this tissue. This is further supported by the association of nuclear KLF4 with an aggressive breast cancer phenotype (16). In contrast, Akaogi et al. reported that a review of nine independent, publicly available gene expression data sets revealed de...

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“…In RNAi experiments, 1 mM of siRNA solution containing a pool of two different siRNA duplexes (GenePharma Co., Ltd.) were used for each well. The sequence of siRNA duplexes was synthesized according to previous reports [11]. In the rescue experiment, NSCs were cotransfected with the Klf4 siRNA and miR-7 inhibitors at the same time.…”

Section: Transient Transfections and Cell Treatmentsmentioning

confidence: 99%

The miR-7 Identified from Collagen Biomaterial-Based Three-Dimensional Cultured Cells Regulates Neural Stem Cell Differentiation

Cui

Xiao

Chen

et al. 2014

Stem Cells and Development

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Increasing evidence suggests that three-dimensional (3D) cultures provide more appropriate microenvironments to control stem cell response compared with traditional two-dimensional (2D) cultures. However, the molecular mechanism involved in 3D cultured stem cells is not well known. Several microRNAs whose target genes involved in the regulation of self-renewal and differentiation of stem cells were found to be downregulated in 3D cultured PA-1 cells. Among them, miR-7 was predicted to target Kruppel-like factor 4 (Klf4), a key gene for self-renewal of neural stem cells (NSCs). We showed that the differentiation of NSCs was inhibited in 3D collagen scaffolds compared with 2D cultured cells. The quantitative real-time PCR (qPCR) analysis indicated that the expression of miR-7 and Klf4 changed significantly in 2D cultures, whereas the expression stability of miR-7 and Klf4 was detected in 3D cultures. Using luciferase assay and western blot, Klf4 was identified as a target of miR-7 indicating that miR-7 plays a critical role in maintaining the selfrenewal capacity through a Klf4-dependent mechanism in 3D cultured cells. Thus, the collagen scaffold-based 3D cell cultures may provide a platform to reveal the regulatory mechanism of cell regulators, which are difficult to find in traditional 2D cell cultures.

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KLF4 suppresses estrogen-dependent breast cancer growth by inhibiting the transcriptional activity of ERα

Cited by 100 publications

References 46 publications

Critical and Reciprocal Regulation of KLF4 and SLUG in Transforming Growth Factor β-Initiated Prostate Cancer Epithelial-Mesenchymal Transition

Critical and Reciprocal Regulation of KLF4 and SLUG in Transforming Growth Factor β-Initiated Prostate Cancer Epithelial-Mesenchymal Transition

Krüppel-like Factor 4 Inhibits Epithelial-to-Mesenchymal Transition through Regulation of E-cadherin Gene Expression

The miR-7 Identified from Collagen Biomaterial-Based Three-Dimensional Cultured Cells Regulates Neural Stem Cell Differentiation

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