MYC and integrins interplay in colorectal cancer.

The proto-oncogene MYC is one of several well-known transcription factors involved in the genesis and progression of many types of cancer acting as a main regulator of the expression of genes involved in cell proliferation, invasion, apoptosis, metabolism, DNA repair and protein synthesis [1, 2]. Different mechanisms are involved in the deregulation of MYC expression in cancer including gene mutation and amplification as well as upregulation by activated upstream pathways namely WNT/APC/β-catenin and receptor tyrosine kinase(RTK)/ RAS/MEK/ERK pathways [1], both frequently activated in colorectal cancer (CRC). Defects in the former pathway prevent β-catenin phosphorylation by GSK3β kinase allowing β-catenin translocation to the nucleus where it can enhance MYC transcription by binding to TCF on the MYC promoter. GSK3β inhibition also prevents MYC phosphorylation at threonine 58 preventing its degradation while MYC phosphorylation on serine 62 by ERK favors its stabilization. These two sets of events illustrate the potential regulation of MYC expression in CRC cells. The regulation of gene transcription by MYC has also been reviewed in detail [1, 2]. Essentially, MYC functions as a transcriptional regulator in association with its partner MAX; the MYC/MAX heterodimer binds to DNA in a sequence-specific manner to activate transcription. Studies over the last decade have identified and characterized several additional partners defined as the MYC/MAX/MAD network that cooperate in the modulation of MYC transcriptional activity [2]. The MYC/MAX heterodimer binds to the consensus sequence 5'-CANNTG-3' (E box) to regulate the transcription of genes [1]. The occurrence of canonical MYC E-box motifs is high in the human genome. While they can be bound by other E box transcription factors in non-proliferating cells for basal cell metabolism, binding of the E box by MYC/ MAX appears to be favoured in cells displaying high levels of MYC, leading to a change in metabolism [1]. Integrins are among the genes regulated by MYC. For instance, ITGA6, ITGB1 and ITGB4 promoters contain a canonical E box binding site for MYC. In the mouse skin, MYC represses Itga6, Itgb1 and Itgb4 expression via the formation of a complex with MIZ1, which mediates MYC repression of gene expression [3]. However, in CRC cells, MYC positively regulates ITGA6 (Groulx et al., unpublished) and ITGB4 [4] expression supporting the notion that MYC transcriptional activity is cell context-dependent. A recent study from our group identified another integrin subunit upregulated in colorectal cancer and in colorectal tumour cell lines: ITGA1 [5]. In order to …