Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843, USA.
Mol Cancer Ther. 2012 Jul;11(7):1421-31. doi: 10.1158/1535-7163.MCT-12-0026. Epub 2012 May 2.
Treatment of ErbB2-overexpressing BT474 and MDA-MB-453 breast cancer cells with 1 to 10 μmol/L betulinic acid inhibited cell growth, induced apoptosis, downregulated specificity protein (Sp) transcription factors Sp1, Sp3, and Sp4, and decreased expression of ErbB2. Individual or combined knockdown of Sp1, Sp3, Sp4 by RNA interference also decreased expression of ErbB2 and this response was because of repression of YY1, an Sp-regulated gene. Betulinic acid-dependent repression of Sp1, Sp3, Sp4, and Sp-regulated genes was due, in part, to induction of the Sp repressor ZBTB10 and downregulation of microRNA-27a (miR-27a), which constitutively inhibits ZBTB10 expression, and we show for the first time that the effects of betulinic acid on the miR-27a:ZBTB10-Sp transcription factor axis were cannabinoid 1 (CB1) and CB2 receptor-dependent, thus identifying a new cellular target for this anticancer agent.
用 1 至 10μmol/L 的白桦脂酸处理过表达 ErbB2 的 BT474 和 MDA-MB-453 乳腺癌细胞，抑制细胞生长，诱导细胞凋亡，下调特异性蛋白（Sp）转录因子 Sp1、Sp3 和 Sp4，并降低 ErbB2 的表达。通过 RNA 干扰单独或联合敲低 Sp1、Sp3、Sp4 也降低了 ErbB2 的表达，这是由于 Sp 调节基因 YY1 的抑制。白桦脂酸依赖的 Sp1、Sp3、Sp4 和 Sp 调节基因的抑制部分是由于 Sp 抑制剂 ZBTB10 的诱导和 microRNA-27a（miR-27a）的下调，miR-27a 持续抑制 ZBTB10 的表达，我们首次表明白桦脂酸对 miR-27a：ZBTB10-Sp 转录因子轴的作用依赖于大麻素 1（CB1）和 CB2 受体，从而确定了这种抗癌剂的新细胞靶标。
