Krüppel-like Transcription Factor-10 (KLF10) Provides a Negative Feedback Mechanism to Suppress TGFβ-Induced Epithelial-to-Mesenchymal Transition
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE90567 | GEO | 2017/03/14
SECONDARY ACCESSION(S): PRJNA355088
REPOSITORIES: GEO
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2017-03-14 | GSE90566 | GEO
Project description:We have elucidated the potential role of KLF10 in inhbiting TGFβ-induced EMT. Further, we show that KLF10 directly binds to SNAI2 and recruit HDAC1 to inhbit the expression of SNAI2.
2017-03-14 | GSE90565 | GEO
Project description:Krüppel-like Transcription Factor-10 (KLF10) Provides a Negative Feedback Mechanism to Suppress TGFβ-Induced Epithelial-to-Mesenchymal Transition
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Project description:TGF?-SMAD signaling exerts a contextual effect that suppresses malignant growth early in epithelial tumorigenesis but promotes metastasis at later stages. Longstanding challenges in resolving this functional dichotomy may uncover new strategies to treat advanced carcinomas. The Krüppel-like transcription factor, KLF10, is a pivotal effector of TGF?/SMAD signaling that mediates antiproliferative effects of TGF?. In this study, we show how KLF10 opposes the prometastatic effects of TGF? by limiting its ability to induce epithelial-to-mesenchymal transition (EMT). KLF10 depletion accentuated induction of EMT as assessed by multiple metrics. KLF10 occupied GC-rich sequences in the promoter region of the EMT-promoting transcription factor SLUG/SNAI2, repressing its transcription by recruiting HDAC1 and licensing the removal of activating histone acetylation marks. In clinical specimens of lung adenocarcinoma, low KLF10 expression associated with decreased patient survival, consistent with a pivotal role for KLF10 in distinguishing the antiproliferative versus prometastatic functions of TGF?. Our results establish that KLF10 functions to suppress TGF?-induced EMT, establishing a molecular basis for the dichotomy of TGF? function during tumor progression. Cancer Res; 77(9); 2387-400. ©2017 AACR.
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Project description:Diabetic nephropathy is the leading cause of end-stage renal disease. Although dysfunction of podocytes, also termed glomerular visceral epithelial cells, is critically associated with diabetic nephropathy, the mechanism underlying podocyte dysfunction still remains obscure. Here, we identify that KDM6A, a histone lysine demethylase, reinforces diabetic podocyte dysfunction by creating a positive feedback loop through up-regulation of its downstream target KLF10. Overexpression of KLF10 in podocytes not only represses multiple podocyte-specific markers including nephrin, but also conversely increases KDM6A expression. We further show that KLF10 inhibits nephrin expression by directly binding to the gene promoter together with the recruitment of methyltransferase Dnmt1. Importantly, inactivation or knockout of either KDM6A or KLF10 in mice significantly suppresses diabetes-induced proteinuria and kidney injury. Consistent with the notion, we also show that levels of both KDM6A and KLF10 proteins or mRNAs are substantially elevated in kidney tissues or in urinary exosomes of human diabetic nephropathy patients as compared with control subjects. Our findings therefore suggest that targeting the KDM6A-KLF10 feedback loop may be beneficial to attenuate diabetes-induced kidney injury.
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Project description:Diabetic nephropathy is the leading cause of end-stage renal disease. Although dysfunction of podocytes, also termed glomerular visceral epithelial cells, is critically associated with diabetic nephropathy, the mechanism underlying podocyte dysfunction still remains obscure. Here, we identify that KDM6A, a histone lysine demethylase, reinforces diabetic podocyte dysfunction by creating a positive feedback loop through up-regulation of its downstream target KLF10. Overexpression of KLF10 in podocytes not only represses multiple podocyte-specific markers including nephrin, but also conversely increases KDM6A expression. We further show that KLF10 inhibits nephrin expression by directly binding to the gene promoter together with the recruitment of methyltransferase Dnmt1. Importantly, inactivation or knockout of either KDM6A or KLF10 in mice significantly suppresses diabetes-induced proteinuria and kidney injury. Consistent with the notion, we also show that levels of both KDM6A and KLF10 proteins or mRNAs are substantially elevated in kidney tissues or in urinary exosomes of human diabetic nephropathy patients as compared with control subjects. Our findings therefore suggest that targeting the KDM6A-KLF10 feedback loop may be beneficial to attenuate diabetes-induced kidney injury.
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