The Wnt-β-catenin signaling regulated MRTF-A transcription to activate migration-related genes in human breast cancer cells

Abstract

MRTF-A is a transcriptional co-activator being critical for multiple processes including tissue fibrosis and cancer metastasis. The Rho-actin signaling stimulates the nuclear translocation and transcriptional activity of MRTF-A with little effect on the expression of MRTF-A gene. High expression of MRTF-A was observed in pancreatic cancer tissues and in TGF-β treated breast cancer cells. However, the mechanism for the upregulation of MRTF-A gene remains unclear. In this study, we showed that the transcription of MRTF-A was regulated by the Wnt-β-catenin signaling in breast cancer cells. LiCl treatment, Wnt3a treatment or β-catenin overexpression enhanced the transcription of MRTF-A gene. In agreement, depletion of β-catenin with siRNA diminished MRTF-A transcription. With ChIP assays, β-catenin was identified to interact with the MRTF-A promoter whereby it increased histone H4 acetylation and RNA polymerase II association. Further, results of RT-qPCR and Western-blotting supported that the transcriptional co-activator activity of MRTF-A was controlled by both the Rho-actin and the Wnt-β-catenin signaling pathways. MRTF-A was required for cell migration stimulated by the Wnt-β-catenin signaling. Taken together, our results suggest that MRTF-A integrates the Rho-actin and the Wnt-β-catenin signaling to regulate migration-related genes and consequently increases the mobility of breast cancer cells.

MRTF: Basic Biology and Role in Kidney Disease

“…MRTF is also regulated at the transcriptional level, although the underlying mechanisms remain largely uncharacterized. Nonetheless, β-catenin has been recently identified as an inducer of the MRTF gene [ 127 ], suggesting that β-catenin not only stabilizes MRTF but also enhances its synthesis. While this observation was made in a tumor context, it may well be relevant in organ fibrosis as well.…”

MRTF-A-NF-κB/p65 axis-mediated PDL1 transcription and expression contributes to immune evasion of non-small-cell lung cancer via TGF-β

“…Noncanonical pathways include RhoA/ROCK1, PI3K/Akt, Wnt/β-catenin, MAPK/p38, or MAPK ERK1/2, all of which mediate different effects of TGF-β on tumor cells 35 , 45 , 46 . Thus, we assessed the TGF-β-induced change in PD-L1 expression in the absence or presence of various inhibitors, including the selective p38 MAPK inhibitor doramapimod (DORA), the Akt inhibitor AKTi-1/2 (AKTi), the MEK inhibitor U0126, the Rho kinase inhibitor Y-27632 and β-catenin siRNA.…”

“…4i ). It has been reported that β-catenin and Rho can regulate the expression and nuclear localization of MRTF-A, respectively 35 , 47 . AKT and p38 provoke the phosphorylation and consequent activation of p65 48 , 49 .…”

“…Under basal conditions, MRTF-A binds to G-actin, preventing it from translocating to the nucleus 31 . Activation of the RhoA and TGF-β signaling pathways can induce the translocation of MRTF-A to the nucleus 32 , where it promotes the expression of EMT-related molecules and thus enhances the adhesion, migration, and invasion of tumor cells 32 – 35 . However, it is still unknown whether MRTF-A is a key coordinator in tumor immune responses.…”

Association Between AXIN1 Gene Polymorphisms and Epithelial Ovarian Cancer in Chinese Population

“…This pathway is critical in human tumorigenesis by regulating cellular proliferation and differentiation in vertebrates as well as invertebrates via the β-catenin destruction complex [5]. Impaired regulation of the Wnt-dependent target genes has been shown to be involved in the occurrence of several other human cancers and its abnormal expression has been associated with tumorigenesis, for example, breast cancer, endometrial cancer [7], colon carcinoma [8], medulloblastoma [9], melanoma [10], hepatocellular carcinoma [11] and gastric cancer [12]. In addition, studies have shown that complete inactivation of AXIN1 function led to early embryonic lethality in mice.…”