Novel insight into KLF4 proteolytic regulation in estrogen receptor signaling and breast carcinogenesis

Dong Hu, Zhuan Zhou, Nancy E. Davidson, Yi Huang, Yong Wan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Krüppel-like factor 4 (KLF4), a zinc finger-containing transcriptional factor, is a pivotal regulator of cellular fate. KLF4 has attracted considerable attention for its opposing effect in carcinogenesis as tumor suppressor (e.g. colorectal cancer) or oncoprotein (e.g. breast cancer), depending on tissue context, with the underlying mechanism remaining largely unknown. Here we report that KLF4 mediates estrogen signaling in breast cancer formation. Accumulation of KLF4 by inhibiting its turnover triggers estrogen-induced transactivation. We identified Von Hippel-Lindau, pVHL, as the protein that governs KLF4 turnover in breast cancer cells and demonstrated that estrogen-induced down-regulation of pVHL facilitates accumulation of KLF4. We provide mechanistic insights into KLF4 steady-state degradation as well as its elevation in the presence of estrogen and show that elevated levels of pVHL or depletion of KLF4 attenuates the estrogen-induced transactivation and cell growth. Finally, immunohistochemical staining revealed reduced concentration of pVHL and accumulation of KLF4 in breast cancer tissues. We thus propose that suppression of pVHL in response to estrogen signaling results in elevation of KLF4, which mediates estrogen-induced mitogenic effect.

Original languageEnglish (US)
Pages (from-to)13584-13597
Number of pages14
JournalJournal of Biological Chemistry
Volume287
Issue number17
DOIs
StatePublished - Apr 20 2012

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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