The double life of KLF5: Opposing roles in regulation of gene-expression, cellular function, and transformation

Diakiw, Sonya M.; D’Andrea, Richard J.; Brown, Anna L.

doi:10.1002/iub.1233

Cited by 57 publications

(55 citation statements)

References 114 publications

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“…For instance, expression of KLF5 enhances cell proliferation in untransformed cells and transformed fibroblasts, whereas KLF5 suppresses cell growth in some cancer cells (28). Recent reports disclosed that xenograft tumor growth was suppressed by the expression of wild-type KLF5 but enhanced by the expression of a deacetylated KLF5 mutant (K369R) in prostate cancer cells, suggesting that the roles of KLF5 are regulated by posttranscriptional modifications (53).…”

Section: Discussionmentioning

confidence: 99%

“…We previously reported that prostate tumor growth is regulated through the ER␤-dependent nonclassical pathway with Krüppel-like zinc finger transcription factor 5 (KLF5) (25). KLF5 (also known as BTEB2 or IKLF) is a transcription factor that possesses both tumor-suppressing and tumor-promoting activities (26)(27)(28). Analysis of the associated pathway revealed that in the absence of E2, ER␤ induces the KLF5-mediated expression of FOXO1 and increases anoikis, thereby suppressing prostate tumor growth in mouse xenograft models.…”

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confidence: 99%

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Estrogen Exhibits a Biphasic Effect on Prostate Tumor Growth through the Estrogen Receptor β-KLF5 Pathway

Nakajima

Osakabe

Waku

et al. 2016

Molecular and Cellular Biology

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h Estrogens are effective in the treatment of prostate cancer; however, the effects of estrogens on prostate cancer are enigmatic. In this study, we demonstrated that estrogen (17␤-estradiol [E2]) has biphasic effects on prostate tumor growth. A lower dose of E2 increased tumor growth in mouse xenograft models using DU145 and PC-3 human prostate cancer cells, whereas a higher dose significantly decreased tumor growth. We found that anchorage-independent apoptosis in these cells was inhibited by E2 treatment. Similarly, in vivo angiogenesis was suppressed by E2. Interestingly, these effects of E2 were abolished by knockdown of either estrogen receptor ␤ (ER␤) or Krüppel-like zinc finger transcription factor 5 (KLF5). ⌱n addition, E2 suppressed KLF5-mediated transcription through ER␤, which inhibits proapoptotic FOXO1 and proangiogenic PDGFA expression. Furthermore, we revealed that a nonagonistic ER ligand GS-1405 inhibited FOXO1 and PDGFA expression through the ER␤-KLF5 pathway and regulated prostate tumor growth without ER␤ transactivation. Therefore, these results suggest that E2 biphasically modulates prostate tumor formation by regulating KLF5-dependent transcription through ER␤ and provide a new strategy for designing ER modulators, which will be able to regulate prostate cancer progression with minimal adverse effects due to ER transactivation.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Estrogen Exhibits a Biphasic Effect on Prostate Tumor Growth through the Estrogen Receptor β-KLF5 Pathway

Nakajima

Osakabe

Waku

et al. 2016

Molecular and Cellular Biology

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“…Plenty of HIF-1α inhibitors, including chemical inhibitors, protein and nucleic acid agents, have been studied for targeted cancer therapy (26). KLF5 is predominantly present in epithelial tissues characterized by active proliferation and exerts pleiotropic effects on the regulation of tumor progression, cell proliferation and apoptosis by binding to similar GC-rich promoter of target genes (27). In our experiments, expression of HIF-1α and KLF5 was upregulated time-dependently in A549 cells exposed to 1% O 2 .…”

Section: Discussionmentioning

confidence: 99%

KLF5 promotes hypoxia-induced survival and inhibits apoptosis in non-small cell lung cancer cells via HIF-1α

Liu

et al. 2014

International Journal of Oncology

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Abstract. Transcription factor Krüppel-like factors 5 (KLF5) is overexpressed in a wide range of tumor tissues and acts as a prognostic factor in cancer. However, the role of KLF5 in non-small cell lung cancer is not clear. Hypoxia plays a vital part in the development of cancer via hypoxia-inducible factor 1 (HIF-1). Our study showed that hypoxia (1% O 2 ) increased cell viability, clonality and proliferation and inhibited cell apoptosis in A549 cells. The expression of HIF-1α and KLF5 was increased time-dependently in hypoxia. Using small interfering RNA (siRNA) targeting KLF5 or HIF-1α, we demonstrated that KLF5 or HIF-1α knockdown inhibited hypoxia-induced cell survival and promoted cell apoptosis by actively downregulating cyclin B1, survivin and upregulating caspase-3. Given the similar effect of KLF5 and HIF-1α on cell survival, an attempt was made to investigate the putative interaction of them in hypoxia. KLF5 was revealed to co-immunoprecipitate with HIF-1α and hypoxia increased the amount of KLF5 and HIF-1α complex. Moreover, silencing of KLF5 decreased HIF-1α expression while KLF5 was not affected by HIF-1α inhibition in hypoxia, confirming the effect of KLF5 on upregulation of HIF-1α. In conclusion, this study identified hypoxia as a tumor promoter by triggering KLF5 → HIF-1α → cyclin B1/survivin/caspase-3 in lung cancer cells.

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“…KLF5 is part of the Kruppel-like family of transcription factors, composed of 17 members, with diverse activities in several biological processes such as cellular proliferation, metabolism, stress response, among others (Diakiw et al, 2013;Farrugia et al, 2016). KLF5 holds stable expression throughput embryonic development in mice and is required for maintenance of pluripotency (Ema et al, 2008;Parisi and Russo, 2011).…”

Section: Kruppel-like Factor 5 (Klf5)mentioning

confidence: 99%

Lessons learned from functional assessment of pluripotency-associated transcription factors during early embryogenesis and embryonic stem cells

et al. 2017

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Pluripotency-associated transcription factors (PATF) play significant roles during early embryogenesis and in embryonic stem (ES) cells, such as control of cell-cycle progression, modulation of cellular metabolism, and transcriptional control of differentiation-inducing factors. The review aims to describe the current understanding of how these PATFs contribute to the early embryo and the ES-cell phenotypes. By a selection of representative examples of such PATFs, their roles are described, and some interesting questions are presented concerning their activity in pluripotent cells which have yet to be addressed.Keywords: embryology; pluripotent; preimplantation development; totipotency. ResumoFatores de transcrição relacionados à pluripotência (FTRP) apresentam importantes funções durante a embriogênese inicial e em células-tronco embrionárias (CTE), como o controle da progressão do ciclo celular, modulação do metabolismo celular e controle transcricional de fatores indutores de diferenciação celular. O objetivo da revisão foi descrever o conhecimento vigente sobre como estes FTRPs contribuem para o fenótipo dos embriões e CTEs. Através da seleção de exemplos representativos destes FTRPs, suas funções são descritas e algumas perguntas interessantes são apresentadas considerando suas atividades em células pluripotentes, mas que ainda não foram devidamente respondidas.Palavras-Chave: embriologia; pluripotente; desenvolvimento pré-implantacional; totipotência.

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The double life of KLF5: Opposing roles in regulation of gene-expression, cellular function, and transformation

Cited by 57 publications

References 114 publications

Estrogen Exhibits a Biphasic Effect on Prostate Tumor Growth through the Estrogen Receptor β-KLF5 Pathway

Estrogen Exhibits a Biphasic Effect on Prostate Tumor Growth through the Estrogen Receptor β-KLF5 Pathway

KLF5 promotes hypoxia-induced survival and inhibits apoptosis in non-small cell lung cancer cells via HIF-1α

Lessons learned from functional assessment of pluripotency-associated transcription factors during early embryogenesis and embryonic stem cells

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