MENA Is a Transcriptional Target of the Wnt/Beta-Catenin Pathway

Abstract

Wnt/β-catenin signalling pathway plays important roles in embryonic development and carcinogenesis. Overactivation of the pathway is one of the most common driving forces in major cancers such as colorectal and breast cancers. The downstream effectors of the pathway and its regulation of carcinogenesis and metastasis are still not very well understood. In this study, which was based on two genome-wide transcriptomics screens, we identify MENA (ENAH, Mammalian enabled homologue) as a novel transcriptional target of the Wnt/β-catenin signalling pathway. We show that the expression of MENA is upregulated upon overexpression of degradation-resistant β-catenin. Promoters of all mammalian MENA homologues contain putative binding sites for Tcf4 transcription factor – the primary effector of the Wnt/β-catenin pathway and we demonstrate functionality of these Tcf4-binding sites using luciferase reporter assays and overexpression of β-catenin, Tcf4 and dominant-negative Tcf4. In addition, lithium chloride-mediated inhibition of GSK3β also resulted in increase in MENA mRNA levels. Chromatin immunoprecipitation showed direct interaction between β-catenin and MENA promoter in Huh7 and HEK293 cells and also in mouse brain and liver tissues. Moreover, overexpression of Wnt1 and Wnt3a ligands increased MENA mRNA levels. Additionally, knock-down of MENA ortholog in D. melanogaster eyeful and sensitized eye cancer fly models resulted in increased tumor and metastasis formations. In summary, our study identifies MENA as novel nexus for the Wnt/β-catenin and the Notch signalling cascades.

The pattern of hMENA isoforms is regulated by TGF-β1 in pancreatic cancer and may predict patient outcome

“…S5B). Since, β -catenin has been reported as a transcriptional regulator of MENA expression ( 28 and our data presented here) (Fig. S5C), we hypothesized that it may be directly involved in TGF-β1-induced hMENA mRNA upregulation.…”

“…Consistent with the opposite roles of hMENA isoforms in cancer cell invasiveness 14 and in patient prognosis, our findings revealed that TGF-β1 upregulates Iso-Δv6 but not Iso-11a, although TGF-β1 increases the expression of hMENA mRNAs both in epithelial and mesenchymal cell lines. This upregulation requires β-catenin expression, given its role as a transcriptional regulator of hMENA 28 . This isoform regulation seems to be specific to TGF-β1 and did not occur after the inhibition of GSK3β that participate in the activation of the Wnt/β-Catenin pathway, suggesting that, although the two pathways cooperate in hMENA gene expression, TGF-β1 regulates hMENA isoforms at different levels.…”

A Requirement for Mena, an Actin Regulator, in Local mRNA Translation in Developing Neurons

“…Interestingly, some of the Mena-complex associated mRNAs encode proteins that have been functionally linked to Mena (e.g. Vamp2 (Gupton and Gertler, 2010), Robo1 (Bashaw et al, 2000; McConnell et al, 2016; Yu et al, 2002), Ctnnb1 (Najafov et al, 2012)), while others represent processes not previously associated with Mena (e.g. Khsrp, Elavl1, Eif4ebp2, Dyrk1a, etc).…”

“…Mena-regulated translation of β-catenin could also affect mena mRNA abundance since β-catenin can regulate mena transcription (Najafov et al, 2012). These findings are consistent with the potential existence of regulatory feedback loops that control Mena protein abundance at the transcriptional and translational levels.…”

Downregulation of β-catenin decreases the tumorigenicity, but promotes epithelial-mesenchymal transition in breast cancer cells

“…[8] The downstream effectors of the Wnt/β-catenin signaling pathway and its regulation of carcinogenesis and metastasis, such as colorectal and breast cancers, are still not very well-understood. [9,10] It is now evident that epithelial-mesenchymal transition (EMT) is a crucial mechanism for the acquisition of migratory and invasive ability by epithelial cancer cells. [11] In many types of epithelial cancers, the ability to undergo metastasis has been associated with a loss of epithelial features and acquisition of mesenchymal properties resulting in migration of cancer cells, a process known as EMT.…”