MiR-22, regulated by MeCP2, suppresses gastric cancer cell proliferation by inducing a deficiency in endogenous S-adenosylmethionine
Authors: Tong, Dongdong; Zhang, Jing; Wang, Xiaofei; Li, Qian; Liu, Liying; Lu, Axin; Guo, Bo; Yang, Juan; Ni, Lei; Qin, Hao; Zhao, Lingyu; Huang, Chen
This study investigated the effect of methyl-CpG-binding protein 2 (MeCP2) on miRNA transcription. Our results of miRNA chip assay and ChIP-seq showed that MeCP2 inhibited the expressions of numerous miRNAs by binding to their upstream elements, including not only the promoter but also the distal enhancer. Among the affected miRNAs, miR-22 was identified to remarkably suppress gastric cancer (GC) cell proliferation, arrest G1-S cell cycle transition, and induce cell apoptosis by targeting MeCP2, MTHFD2, and MTHFR. Understanding GC metabolism characteristics is the key to developing novel therapies that target GC metabolic pathways. Our study revealed that the metabolic profiles in GC tissues were altered. SAM (S-adenosylmethionine), a universal methyl donor for histone and DNA methylation, which is specifically involved in the epigenetic maintenance of cancer cells, was found increased. The production of SAM is promoted by the folate cycle. Knockdown of MTHFD2 and MTHFR, two key enzymes in folate metabolism and methyl donor SAM production, significantly suppressed GC cell proliferation. MiR-22 overexpression reduced the level of endogenous SAM by suppressing MTHFD2 and MTHFR, inducing P16, PTEN, and RASSF1A hypomethylation. In conclusion, our study suggests that miR-22 was inhibited by MeCP2, resulting in deficiency of endogenous SAM, and ultimately leading to tumor suppressor dysregulation.
Histone deacetylase 6 inhibition mitigates renal fibrosis by suppressing TGF-beta and EGFR signaling pathways in obstructive nephropathy
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
Authors: Chen, Xingying; Yu, Chao; Hou, Xiying; Li, Jialu; Li, Tingting; Qiu, Andong; Liu, Na; Zhuang, Shougang
We have recently shown that histone deacetylase 6 (HDAC6) is critically involved in the pathogenesis of acute kidney injury. Its role in renal fibrosis, however, remains unclear. In this study, we examined the effect of ricolinostat (ACY-1215), a selective inhibitor of HDAC6, on the development of renal fibrosis in a murine model induced by unilateral ureteral obstruction (UUO). HDAC6 was highly expressed in the kidney following UUO injury, which was coincident with deposition of collagen fibrils and expression of alpha-smooth muscle actin, libronectin, and collagen type III. Administration of ACY-1215 reduced these fibrotic changes and inhibited UUO-induced expression of transforming growth factor-beta 1 and phosphorylation of Smad3 while increasing expression of Smad7. ACY-1215 treatment also suppressed phosphorylation of epidermal growth factor receptor (EGFR) and several signaling molecules associated with renal fibrogenesis, including AKT, STAT3, and NF-kappa B in the injured kidney. Furthermore, ACY-1215 was effective in inhibiting dedifferentiation of renal fibroblasts to myofibroblasts and the fibrotic change of renal tubular epithelial cells in culture. Collectively, these results indicate that HDAC6 inhibition can attenuate development of renal fibrosis by suppression of transforming growth factor-beta 1 and EGFR signaling and suggest that HDAC6 would be a potential therapeutic target for the treatment of renal fibrosis.