Department of Medical Pathology and Laboratory Medicine, University of California, Davis Health System, Sacramento, California, USA.
Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, California, USA.
FASEB J. 2019 Feb;33(2):2314-2326. doi: 10.1096/fj.201801390R. Epub 2018 Sep 25.
This study investigates the mechanism and consequences of microRNA-22 ( miR-22) induction. Our data revealed for the first time that retinoic acid (RA) and histone deacetylase (HDAC) inhibitors, including short-chain fatty acids and suberanilohydroxamic acid (SAHA), could individually or in combination induce miR-22. This induction was mediated via RA receptor β (RARβ) binding to a direct repeat 5 (DR5) motif. In addition, we uncovered HDAC1 as a novel miR-22 target. In an miR-22-dependent manner, HDAC inhibitors and RA reduced HDAC1, HDAC4, and sirtuin 1 (SIRT1), which were involved in chromatin remodeling of the RARβ and nerve growth factor IB ( NUR77). Thus, HDAC inhibitors and RA-induced miR-22 resulted in simultaneous induction of cytoplasmic RARβ and NUR77, leading to apoptosis of colon cancer cells. In mice, miR-22 and its inducers inhibited the growth of xenograft colon cancer. Moreover, tumor size reduction was accompanied by elevated miR-22, NUR77, and RARβ and by reduced HDACs. In human colon polyps and adenocarcinomas, miR-22 and RARβ were consistently reduced, which was associated with elevated HDAC1, HDAC4, and SIRT1 in colon adenocarcinomas. Results from this study revealed a novel anticancer mechanism of RARβ via miR-22 induction to epigenetically regulate itself and NUR77, providing a promising cancer treatment modality using miR-22 and its inducers.-Hu, Y., French, S. W., Chau, T., Liu, H.-X., Sheng, L., Wei, F., Stondell, J., Garcia, J. C., Du, Y., Bowlus, C. L., Wan, Y.-J. Y. RARβ acts as both an upstream regulator and downstream effector of miR-22, which epigenetically regulates NUR77 to induce apoptosis of colon cancer cells.
这项研究调查了 microRNA-22（miR-22）诱导的机制和后果。我们的数据首次揭示，维 A 酸（RA）和组蛋白去乙酰化酶（HDAC）抑制剂，包括短链脂肪酸和 suberanilohydroxamic 酸（SAHA），可以单独或联合诱导 miR-22。这种诱导是通过 RA 受体 β（RARβ）与直接重复 5（DR5）基序结合介导的。此外，我们发现 HDAC1 是 miR-22 的一个新靶标。在 miR-22 依赖的方式中，HDAC 抑制剂和 RA 降低了 HDAC1、HDAC4 和 Sirtuin 1（SIRT1），它们参与了 RARβ 和神经生长因子 IB（NUR77）的染色质重塑。因此，HDAC 抑制剂和 RA 诱导的 miR-22 导致 RARβ 和 NUR77 的细胞质同时诱导，导致结肠癌细胞凋亡。在小鼠中，miR-22 和其诱导剂抑制异种移植结肠癌细胞的生长。此外，肿瘤体积减小伴随着 miR-22、NUR77 和 RARβ 的升高，以及 HDACs 的降低。在人类结肠息肉和腺癌中，miR-22 和 RARβ 一致降低，这与结肠腺癌中 HDAC1、HDAC4 和 SIRT1 的升高有关。这项研究的结果揭示了 RARβ 通过 miR-22 诱导来表观遗传调控自身和 NUR77 的一种新的抗癌机制，为使用 miR-22 和其诱导剂提供了一种有前途的癌症治疗方式。-Hu, Y., French, S. W., Chau, T., Liu, H.-X., Sheng, L., Wei, F., Stondell, J., Garcia, J. C., Du, Y., Bowlus, C. L., Wan, Y.-J. Y. RARβ 既是 miR-22 的上游调节剂，也是下游效应物，miR-22 通过表观遗传调控 NUR77 诱导结肠癌细胞凋亡。
