ATRA activates and PDGF‐BB represses the SM22α promoter through KLF4 binding to or dissociating from its cis‐DNA elements

Phenotypic modulation of vascular smooth muscle cells (VSMCs) is associated with the expression of VSMC differentiation marker genes including SM22a. It is known that all‐trans retinoic acid (ATRA) increases and platelet‐derived growth factor‐BB (PDGF‐BB) decreases the SM22a expression. Krupel‐like factor 4 (KLF4) is implicated in the regulation of VSMC differentiation marker genes. However, little is known about the role and action mechanism of KLF4 in the expression of SM22a in the context of ATRA and PDGF‐BB. In this study, we showed that both ATRA and PDGF‐BB induce KLF4 expression but exhibit an opposite effect on SM22a expression. Similarly, ATRA promotes but PDGF‐BB represses the binding of KLF4 to the SM22a promoter. The SM22a promoter region from ?676 to +1 contains a typical KLF4‐binding site site 1 and its reverse orientation sequence site 2. Chromatin immunoprecipitation and oligonucleotide pull‐down assays showed that ATRA increases the binding of KLF4 to site 2, whereas PDGF‐BB decreases the binding of KLF4 to site 1. Further study demonstrated that ATRA induces KLF4 acetylation via JNK and p38 pathways, while PDGF‐BB induces KLF4 deacetylation via PI3K/Akt and ERK pathways. These results suggest that KLF4 regulates the SM22a promoter activity via its interaction with different cis‐elements in an acetylation‐dependent manner in the context of ATRA and PDGF‐BB.