Krüppel-like transcription factor KLF10 suppresses TGFβ-induced epithelial-to-mesenchymal transition via a negative feedback mechanism

Vivek Kumar Mishra, Malayannan Subramaniam, Vijayalakshmi Kari, Kevin S. Pitel, Simon J. Baumgart, Ryan M. Naylor, Sankari Nagarajan, Florian Wegwitz, Volker Ellenrieder, John R Hawse, Steven Johnsen

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2387-2400
Number of pages14
JournalCancer Research
Volume77
Issue number9
DOIs
StatePublished - May 1 2017

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Epithelial-Mesenchymal Transition
Transcription Factors
Histone Code
GC Rich Sequence
Licensure
Acetylation
Genetic Promoter Regions
Carcinogenesis
Neoplasm Metastasis
Carcinoma
Survival
Growth
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Krüppel-like transcription factor KLF10 suppresses TGFβ-induced epithelial-to-mesenchymal transition via a negative feedback mechanism. / Mishra, Vivek Kumar; Subramaniam, Malayannan; Kari, Vijayalakshmi; Pitel, Kevin S.; Baumgart, Simon J.; Naylor, Ryan M.; Nagarajan, Sankari; Wegwitz, Florian; Ellenrieder, Volker; Hawse, John R; Johnsen, Steven.

In: Cancer Research, Vol. 77, No. 9, 01.05.2017, p. 2387-2400.

Research output: Contribution to journalArticle

Mishra, VK, Subramaniam, M, Kari, V, Pitel, KS, Baumgart, SJ, Naylor, RM, Nagarajan, S, Wegwitz, F, Ellenrieder, V, Hawse, JR & Johnsen, S 2017, 'Krüppel-like transcription factor KLF10 suppresses TGFβ-induced epithelial-to-mesenchymal transition via a negative feedback mechanism', Cancer Research, vol. 77, no. 9, pp. 2387-2400. https://doi.org/10.1158/0008-5472.CAN-16-2589
Mishra, Vivek Kumar ; Subramaniam, Malayannan ; Kari, Vijayalakshmi ; Pitel, Kevin S. ; Baumgart, Simon J. ; Naylor, Ryan M. ; Nagarajan, Sankari ; Wegwitz, Florian ; Ellenrieder, Volker ; Hawse, John R ; Johnsen, Steven. / Krüppel-like transcription factor KLF10 suppresses TGFβ-induced epithelial-to-mesenchymal transition via a negative feedback mechanism. In: Cancer Research. 2017 ; Vol. 77, No. 9. pp. 2387-2400.
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