Regulation of KLF4 Turnover Reveals an Unexpected Tissue-Specific Role of pVHL in Tumorigenesis

SummaryThe transcription factor Krüppel-like factor 4 (KLF4) is an important regulator of cell-fate decision, including cell-cycle regulation, apoptosis, and stem cell renewal, and plays an ambivalent role in tumorigenesis as a tissue-specific tumor suppressor or oncogene. Here, we report that the Von Hippel-Lindau gene product, pVHL, physically interacts with KLF4 and regulates its rapid turnover observed in both differentiated and stem cells. We provide mechanistic insights into KLF4 degradation and show that pVHL depletion in colorectal cancer cells leads to cell-cycle arrest concomitant with increased transcription of the KLF4-dependent p21 gene. Finally, immunohistochemical staining revealed elevated pVHL and reduced KLF4 levels in colon cancer tissues. We therefore propose that unexpectedly pVHL, via the degradation of KLF4, is a facilitating factor in colorectal tumorigenesis.

Graphical AbstractFigure optionsDownload high-quality image (105 K)Download as PowerPoint slideHighlights
► KLF4 physically interacts with the E3 ligase pVHL
► VHL knockout or knockdown leads to increased protein levels of KLF4
► The KLF4 activation domain is the site of ubiquitylation and recognition by pVHL
► KLF4 deregulation by pVHL can play a role in colon tumorigenesis