Kruppel-like factor 4 regulates keratinocyte senescence

Biochem Biophys Res Commun. 2018 May 5;499(2):389-395. doi: 10.1016/j.bbrc.2018.03.172. Epub 2018 Mar 26.


Keratinocyte replicative senescence has an important role in time-related changes of epidermis. Previous studies demonstrated that miRNAs play key roles in inhibiting proliferation and in the acquisition of the keratinocyte senescent phenotype as well as in individual ageing. Kruppel-like factor 4 is a transcription factor with dual functions in keratinocytes, being a stemness factor and a pro-differentiation factor. Interestingly, in skin squamous cell carcinomas KLF4 expression is strongly down-regulated or absent. While KLF4 involvement in senescence and ageing has not been investigated yet. Here, we show that Klf4 protein decreases during keratinocyte replicative senescence and during physiological skin aging, while its mRNA level does not change. We demonstrated that the senescence-associated miR-34a regulates post-transcriptionally Klf4 expression. KLF4 silencing is sufficient to induce a senescent phenotype in primary keratinocytes and ectopic miR-34a over-expression phenocopies this result. Our findings identify a novel regulatory loop between miR-34a and KLF4 during keratinocytes replicative senescence. This regulatory loop, beside aging, may play a role in age-related pathologies.

Keywords: Epidermis; Keratinocytes; Klf4; Senescence; Skin aging; miR-34a.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • Base Sequence
  • Cell Line
  • Cellular Senescence*
  • Down-Regulation / genetics
  • Gene Silencing
  • Humans
  • Keratinocytes / cytology*
  • Keratinocytes / metabolism*
  • Kruppel-Like Factor 4
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism*
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Skin Aging


  • 3' Untranslated Regions
  • KLF4 protein, human
  • Kruppel-Like Factor 4
  • Kruppel-Like Transcription Factors
  • MIRN34 microRNA, human
  • MicroRNAs
  • RNA, Messenger