MicroRNAs miR-199a-5p and -3p target the Brm subunit of SWI/SNF to generate a double-negative feedback loop in a variety of human cancers.

The chromatin remodeling complex SWI/SNF is an important epigenetic regulator that includes one Brm or BRG1 molecule as catalytic subunit. Brm and BRG1 do not function identically, so this complex can regulate gene expression either positively or negatively, depending on the promoter to which it is recruited. Notably, Brm attenuation due to posttranscription suppression occurs often in human tumor cells, in which this event contributes to their oncogenic potential. Here, we report that the 3'-untranslated region of Brm mRNA has two sites that are efficiently targeted by the microRNAs miR-199a-5p and -3p, revealing a novel mechanism for modulation of Brm-type SWI/SNF activity. Computational mapping of the putative promoter region of miR-199a-2 (miPPR-199a-2) has defined it as the major contributing genetic locus for miR-199a-5p and-3p production in these tumor cell lines. We validated this predicted region by direct promoter analysis to confirm that Egr1 is a strong positive regulator of the miR-199a-2 gene. Importantly, we also showed that Egr1, miR-199a-5p, and miR-199a-3p are expressed at high levels in Brm-deficient tumor cell lines but only marginally in Brm-expressing tumor cells. Finally, we also obtained evidence that Brm negatively regulates Egr1. Together, our results reveal that miR-199a and Brm form a double-negative feedback loop through Egr1, leading to the generation of these two distinct cell types during carcinogenesis. This mechanism may offer a partial explanation for why miR-199a-5p and -3p have been reported to be either upregulated or downregulated in a variety of tumors.

Sakurai K ，Furukawa C ，Haraguchi T ，Inada K ，Shiogama K ，Tagawa T ，Fujita S ，Ueno Y ，Ogata A ，Ito M ，Tsutsumi Y ，Iba H ... -  《-》

The miR-199a/Brm/EGR1 axis is a determinant of anchorage-independent growth in epithelial tumor cell lines.

Kobayashi K ，Sakurai K ，Hiramatsu H ，Inada K ，Shiogama K ，Nakamura S ，Suemasa F ，Kobayashi K ，Imoto S ，Haraguchi T ，Ito H ，Ishizaka A ，Tsutsumi Y ，Iba H ... -  《-》

MicroRNA miR-183 functions as an oncogene by targeting the transcription factor EGR1 and promoting tumor cell migration.

Sarver AL ，Li L ，Subramanian S 《-》

SWI/SNF complex is essential for NRSF-mediated suppression of neuronal genes in human nonsmall cell lung carcinoma cell lines.

Watanabe H ，Mizutani T ，Haraguchi T ，Yamamichi N ，Minoguchi S ，Yamamichi-Nishina M ，Mori N ，Kameda T ，Sugiyama T ，Iba H ... -  《ONCOGENE》

The deoxycholic acid targets miRNA-dependent CAC1 gene expression in multidrug resistance of human colorectal cancer.

There is evidence indicating that bile acid is a promoter of colorectal cancer. Deoxycholic acid modifies apoptosis and proliferation by affecting intracellular signaling and gene expression. We are interested in revealing the relationship between deregulated miRNAs and deoxycholic acid in colorectal cancer development. We found that miR-199a-5p was expressed at a low level in human primary colonic epithelial cells treated with deoxycholic acid compared with control, and miR-199a-5p was significantly down-regulated in colorectal cancer tissues. The miR-199a-5p expression in colorectal cancer cells led to the suppression of tumor cell growth, migration and invasion. We further identified CAC1, a cell cycle-related protein expressed in colorectal cancer, as a miR-199a-5p target. We demonstrated that CAC1 is over-expressed in malignant tumors, and cellular CAC1 depletion resulted in cancer growth suppression. HCT-8 cells transfected with a miR-199a-5p mimic or inhibitor had a decrease or increase in CAC1 protein levels, respectively. The results of the luciferase reporter gene analysis demonstrated that CAC1 was a direct miR-199a-5p target. The high miR-199a-5p expression and low CAC1 protein expression reverse the tumor cell drug resistance. We conclude that miR-199a-5p can regulate CAC1 and function as a tumor suppressor in colorectal cancer. Therefore, the potential roles of deoxycholic acid in carcinogenesis are to decrease miR-199a-5p expression and/or increase the expression of CAC1, which contributes to tumorigenesis in patients with CRC. These findings suggest that miR-199a-5p is a useful therapeutic target for colorectal cancer.

Kong Y ，Bai PS ，Sun H ，Nan KJ ，Chen NZ ，Qi XG ... -  《-》