Targeting MYC Translation in Colorectal Cancer

Abstract

Summary:There is a great interest in fi nding ways to inhibit the expression or activity of the "undruggable" MYC, a master regulator of transcription and one of the most deadly oncoproteins in human cancer. In this issue of Cancer Discovery , Wiegering and colleagues fi nd a way of inhibiting translation of MYC in colorectal cancer cells by directly targeting the translation initiation factor eIF4A, resulting in inhibition of MYC-dependent proliferation of colorectal tumor cells in vitro and in vivo. Cancer Discov; 5(7); 701-3. ©2015 AACR . Wiegering et al., p. 768 (7). See related article byThe transcription factor MYC is among the most attractive but also most elusive targets for cancer therapy, and for many years has been believed to be "undruggable." MYC activates or represses transcription of a large group of genes involved in cellular processes such as cell growth, metabolism, apoptosis, and protein synthesis ( 1 ). Deregulation of MYC occurs in more than half of all human tumors and often correlates with aggressive disease, resistance to therapy, and poor prognosis, emphasizing the urgent need to fi nd ways of targeting this pathway. Evidence from mouse models has shown that elimination of MYC function using genetic tools often causes complete and irreversible tumor regression, suggesting that MYC is a promising, although challenging, target for cancer therapy ( 2 ).Several strategies are being pursued to target MYC directly or indirectly ( Fig. 1 ). These include targeting MYC-cofactor interactions essential for MYC function ( 3 ), targeting MYC activity, for instance by inhibiting kinase-dependent activation of MYC ( 3, 4 ), targeting druggable key downstream target gene products of MYC ( 1 , 3 ), or exploiting synthetic lethal interactions involving MYC ( 3 ). Another approach has been to target MYC expression at different levels. For instance, inhibitors of bromodomain-histone interactions were shown to downregulate MYC transcription and inhibit tumor growth in hematopoietic and other tumors ( 3 ). MYC normally turns over rapidly via the ubiquitin-proteasome pathway. After phosphorylation of MYC by GSK3β, the E3 ubiquitin ligase SCF FBXW7 binds and targets MYC for degradation. However, in many tumors, MYC is stabilized by loss of FBXW7 or through PI3K/AKT-mediated inhibitory phosphorylation of GSK3. In the latter case, pharmacologic inhibition of PI3K has been shown to increase MYC turnover ( 1 , 3 ).Targeting MYC mRNA translation is yet another option. Translation initiation is regulated by eukaryotic initiation factors (eIF), including the cap-binding protein eIF4E, the RNA helicase eIF4A, and the scaffolding protein eIF4G (which are all MYC target genes), forming the eIF4F complex that recruits ribosomes to the 5′-cap of mRNA ( Fig. 1 ; ref. 5 ). For some mRNAs, translation can be initiated by an internal ribosomal entry site (IRES) localized in the 5′ untranslated region (5′-UTR) of the mRNAs. The 5′-UTR of MYC mRNA allows for both cap-and IRES-mediated translation, of which the latter is depende...

Inflammation‐dependent overexpression of c‐Myc enhances CRL4DCAF4 E3 ligase activity and promotes ubiquitination of ST7 in colitis‐associated cancer

“…TNF‐α and IL‐6)‐dependent signalling creates a proinflammatory microenvironment, which may initiate CAC . Besides NF‐κB, another transcription factor, c‐Myc, is overexpressed in CRC and controls cell growth, proliferation and differentiation . c‐Myc can up‐regulate multiple cytokines such as IL‐8, IL‐10, TNF‐α and TGF‐β, and these cytokines in turn can induce c‐Myc expression .…”

The long noncoding RNA linc00858 promotes progress of lung cancer through miR-3182/MMP2 axis

“…It has been reported that lncRNA could participate in the initiating and the progress of diseases by interfering with transcription, translation, epigenetic inheritance and some basic process of cell life activities [3]. Previous researches have demonstrated that lncRNAs play a significant role in various types of tumour [4][5][6][7], especially in lung adenocarcinoma [8][9][10]. For example, White and his colleagues characterized the lncRNA landscape in lung cancer and discovered 111 differentially expressed lncRNAs, which were termed as lung cancer-associated lncRNAs (LCALs).…”

“…The epithelial-mesenchymal transition (EMT) is characterized by the loss of cell polarity and cell-cell adhesion in epithelial cells accompanied by the acquisition of migratory and invasive properties and the transition to mesenchymal stem cells [4,13,14]. EMT is essential for numerous developmental processes and human diseases including wound healing, organ fibrosis and the initiation or the metastasis in cancer progression [15][16][17].…”

Transcriptome and Network Dissection of Microsatellite Stable and Highly Instable Colorectal Cancer

“…MYC is a proto-oncogene which involves in many cancers and its significance in the cell cycle, cell proliferation, and various metabolic processes has been reported (Stine et al, 2015). It has been demonstrated that elimination of MYC function can result in tumor regression which indicates its importance as a therapeutic target, however MYC is an elusive target for cancer therapy (Castell and Larsson, 2015). Our results also displayed significant upregulation of MYC in both MSS and MSI-H CRC and its importance as a critical regulator of DEGs involved in cell cycle and various metabolic processes.…”