Activation of cancer-associated fibroblasts (CAFs) promotes tumorigenesis.,Kim et al. show that ATF3 and CSL converge in negative regulation of CAF activation through long-distance chromatin control.,Bromodomain and extra-terminal (BET) inhibitors counteract the effects of ATF3 and CSL loss in CAF activation and cancer-stromal cell expansion.,Cancer-associated fibroblasts (CAFs) are important for tumor initiation and promotion.,CSL, a transcriptional repressor and Notch mediator, suppresses CAF activation.,Like CSL, ATF3, a stress-responsive transcriptional repressor, is down-modulated in skin cancer stromal cells, and Atf3 knockout mice develop aggressive chemically induced skin tumors with enhanced CAF activation.,Even at low basal levels, ATF3 converges with CSL in global chromatin control, binding to few genomic sites at a large distance from target genes.,Consistent with this mode of regulation, deletion of one such site 2 Mb upstream of IL6 induces expression of the gene.,Observed changes are of translational significance, as bromodomain and extra-terminal (BET) inhibitors, unlinking activated chromatin from basic transcription, counteract the effects of ATF3 or CSL loss on global gene expression and suppress CAF tumor-promoting properties in an in vivo model of squamous cancer-stromal cell expansion.,Thus, ATF3 converges with CSL in negative control of CAF activation with epigenetic changes amenable to cancer- and stroma-focused intervention.
The expression levels of miR-365 vary in different malignancies.,Herein, we found that miR-365 was overexpressed in both cells and clinical specimens of cutaneous squamous cell carcinoma (SCC).,We demonstrated that the HaCaTpre-miR-365-2 cell line, which overexpressed miR-365, could induce subcutaneous tumors in vivo.,Antagomir-365, an anti-miR-365 oligonucleotide, inhibited cutaneous tumor formation in vivo, along with G1 phase arrest and apoptosis of cancer cells.,These findings suggest that miR-365 may act as an onco-miR in cutaneous SCC both in vitro and in vivo.,The present study provides valuable insight into the role of miR-365 in cutaneous SCC formation, which can help develop new drug and miR-365 target-based therapies for cutaneous SCC.