Meng Fang, Han Mei, Zheng Bin, Wang Chao, Zhang Rui, Zhang Xin-hua, Wen Jin-kun
Department of Biochemistry and Molecular Biology, Hebei Medical University, Shijiazhuang, PR China.
Biochem Biophys Res Commun. 2009 Sep 11;387(1):13-8. doi: 10.1016/j.bbrc.2009.05.112. Epub 2009 May 30.
The zinc finger transcription factor Krüppel-like factor 4 (KLF4) has been implicated in vascular smooth muscle cell differentiation induced by all-trans retinoic acid (ATRA). However, the molecular mechanism whereby ATRA regulates KLF4 activity is still poorly understood. Here, we show that ATRA-induced histone deacetylase 2 (HDAC2) phosphorylation at Ser424 in VSMCs and inhibited the interaction of HDAC2 with KLF4. Inhibiting JNK by JNK inhibitor SP600125 or knockdown of JNK by JNK siRNA abrogated ATRA-induced HDAC2 phosphorylation and reversed ATRA-induced suppression of the interaction of HDAC2 with KLF4. We further demonstrated that HDAC2 directly deacetylated KLF4, and that KLF4 acetylation and binding activity of KLF4 to the SM22alpha promoter were significantly increased in ATRA-treated VSMCs. Collectively, our results indicate that ATRA induces HDAC2 phosphorylation mediated by JNK signaling, and thus causes HDAC2 dissociation from KLF4, subsequently leading to the increase in KLF4 acetylation.
锌指转录因子Krüppel样因子4（KLF4）与全反式维甲酸（ATRA）诱导的血管平滑肌细胞分化有关。然而，ATRA调节KLF4活性的分子机制仍知之甚少。在此，我们表明ATRA诱导血管平滑肌细胞中组蛋白去乙酰化酶2（HDAC2）在Ser424位点磷酸化，并抑制HDAC2与KLF4的相互作用。用JNK抑制剂SP600125抑制JNK或用JNK siRNA敲低JNK可消除ATRA诱导的HDAC2磷酸化，并逆转ATRA诱导的HDAC2与KLF4相互作用的抑制。我们进一步证明HDAC2直接使KLF4去乙酰化，并且在经ATRA处理的血管平滑肌细胞中，KLF4的乙酰化以及KLF4与SM22α启动子的结合活性显著增加。总体而言，我们的结果表明ATRA诱导由JNK信号介导的HDAC2磷酸化，从而导致HDAC2与KLF4解离，随后导致KLF4乙酰化增加。
