Krüppel-like Transcription Factor KLF10 Suppresses TGFβ-Induced Epithelial-to-Mesenchymal Transition via a Negative
Vivek Kumar Mishra1, Malayannan Subramaniam2, Vijayalakshmi Kari1
1Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen Center for Molecular Biosciences, Göttingen, Germany.
Abstract:
TGFβ-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 TGFβ/SMAD signaling that mediates antiproliferative effects of TGFβ. In this study, we show how KLF10 opposes the prometastatic effects of TGFβ 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 TGFβ. Our results establish that KLF10 functions to suppress TGFβ-induced EMT, establishing a molecular basis for the dichotomy of TGFβ function during tumor progression. Cancer Res; 77(9); 2387-400. ©2017 AACR.
Insights
Krüppel-like factor 10 (KLF10) suppresses the epithelial-to-mesenchymal transition (EMT) induced by transforming growth factor beta (TGFβ). Low KLF10 levels correlate with reduced survival in lung adenocarcinoma patients, highlighting KLF10's role in tumor progression.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Transforming growth factor beta (TGFβ)-SMAD signaling has dual roles in tumorigenesis, suppressing early growth but promoting metastasis later.
- Understanding this dichotomy is crucial for developing effective treatments for advanced carcinomas.
Purpose of the Study:
- To investigate the role of Krüppel-like transcription factor 10 (KLF10) in TGFβ-mediated epithelial-to-mesenchymal transition (EMT).
- To elucidate the molecular mechanisms by which KLF10 influences TGFβ signaling in cancer progression.
Main Methods:
- Assessed EMT induction upon KLF10 depletion using multiple metrics.
- Investigated KLF10 binding to the SLUG/SNAI2 promoter region.
- Analyzed KLF10 recruitment of HDAC1 and its effect on histone acetylation.
- Correlated KLF10 expression with patient survival in lung adenocarcinoma specimens.
Main Results:
- KLF10 depletion significantly accentuated TGFβ-induced EMT.
- KLF10 directly repressed SLUG/SNAI2 transcription by recruiting HDAC1, leading to reduced histone acetylation.
- Low KLF10 expression in lung adenocarcinoma tissues was associated with poorer patient survival.
Conclusions:
- KLF10 acts as a suppressor of TGFβ-induced EMT.
- KLF10 plays a critical role in differentiating the anti-proliferative and pro-metastatic functions of TGFβ.
- KLF10 represents a potential therapeutic target for managing advanced carcinomas.
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