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Transcription Regulation of MYB: a Potential and Novel Therapeutic Target in Cancer

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Transcription Regulation of MYB: a Potential and Novel Therapeutic Target in Cancer Review Article Page 1 of 11 Transcription regulation of MYB: a potential and novel therapeutic target in cancer Partha Mitra1,2 1Pre-clinical Division, Vaxxas Pty. Ltd. Translational Research Institute, Woolloongabba QLD 4102, Australia; 2Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Woolloongabba QLD 4102, Australia Correspondence to: Partha Mitra. Pre-clinical Division, Vaxxas Pty. Ltd. Translational Research Institute, 37 Kent St., Woolloongabba QLD 4102, Australia; Queensland University of Technology, Translational Research Institute, 37 Kent St., Woolloongabba QLD 4102, Australia. Email: [email protected]; [email protected]. Abstract: Basal transcription factors have never been considered as a priority target in the field of drug discovery. However, their unparalleled roles in decoding the genetic information in response to the appropriate signal and their association with the disease progression are very well-established phenomena. Instead of considering transcription factors as such a target, in this review, we discuss about the potential of the regulatory mechanisms that control their gene expression. Based on our recent understanding about the critical roles of c-MYB at the cellular and molecular level in several types of cancers, we discuss here how MLL-fusion protein centred SEC in leukaemia, ligand-estrogen receptor (ER) complex in breast cancer (BC) and NF-κB and associated factors in colorectal cancer regulate the transcription of this gene. We further discuss plausible strategies, specific to each cancer type, to target those bona fide activators/co-activators, which control the regulation of this gene and therefore to shed fresh light in targeting the transcriptional regulation as a novel approach to the future drug discovery in cancer. Keywords: CDK9; transcriptional regulation; P-TEFb complex Submitted Aug 20, 2018. Accepted for publication Aug 29, 2018. doi: 10.21037/atm.2018.09.62 View this article at: http://dx.doi.org/10.21037/atm.2018.09.62 Introduction this protein. A- and B-MYB, the other two members of the MYB family, share extensive sequence homology and gene Mammalian oncogenic transcription factor C-MYB is a transactivation activities with C-MYB. However, in spite of member of the MYB family of proteins, encoded by the the structural and functional similarities, the distinct tissue c-MYB gene, which is located in chromosome 6. The specific expression of MYB family members indicated that 37.85kb long DNA sequence comprises of 15 exons, perhaps they are involved in controlling different regulatory capable of generating multiple splice variants which upon pathways. A-MYB is mostly expressed in highly proliferating translation can produce series of MYB proteins with unique tissues such as developing central nervous system, in c-terminal domain. c-MYB transcription is regulated by an germinal centre B-lymphocytes, in mammary gland ductal attenuation site located within the first intron and plays epithelium and in the testis (1-3). In contrast to that, the a pivotal role in transcription elongation. The 75 kDa expression of B-MYB is not restricted to any tissue types and MYB protein consists of a DNA binding domain at the co-expressed with other MYB proteins (4,5). The expression N-terminal end that recognizes consensus PyAACG/TG of the founder member C-MYB, is predominantly observed sequence motif. Besides DNA binding domain, the negative in immature hematopoietic cells, colonic crypt and breast regulatory domain is located at the C-terminal end and the epithelial cells (6-8). The functional diversities of MYB transactivation domain, which covers the central part of the family members also reflected in the gene depleted mouse protein, plays a major role in determining the activity of model. A severe defect in haematopoietic system, which © Annals of Translational Medicine. All rights reserved. atm.amegroups.com Ann Transl Med 2018;6(22):443 Page 2 of 11 Mitra. Transcriptional regulation and drug discovery leads to the embryonic lethality, was observed in C-MYB colon, which has stem cell niche formed by stem cells null mouse. Deletion of A-MYB impaired mammary gland surrounded by mesenchymal cells. MYB expression observed development and spermatogenesis whereas; B-MYB deletion to be highest at the base of the crypt which is the functional demonstrated an inhibition of the blastocyst formation compartment of stem cells. Tissue specificMYB knockdown (3,9,10). Microarray based global gene expression profile in mice indicated that MYB is required for crypt integrity, analysis also indicated that each member of MYB family normal differentiation, and steady state proliferation (17). controls the expression of a distinct and specific set of Therefore, it could be anticipated that MYB may contribute genes (11), which supports the fundamental idea of the to the self-renewal property of those stem cells. Analysis participation of MYB family members in distinct regulatory of tumours from colorectal carcinoma patients showed a pathways. In this review, we will only focus on C-MYB, its consistent co-relation between high expression of MYB and role in cancer, the tissue specific regulatory mechanisms BCL-xL expression indicating that co-expression of both that control its transcription and possibilities to target those proteins is required for the tumorigenesis (18). In fact, a mechanisms for new therapeutic interventions. high level MYB expression, associated with poor prognosis, is frequently observed in colorectal cancer (19). Approximately, 70% of human BCs are ER-α positive MYB in cancers (ER+ve) and expression of MYB is observed in almost all Over the last decade, implementation of advanced molecular ER+ve breast tumours. High level of MYB expression also biology and gene manipulation technologies in both in vitro observed in 30% of hereditary BRCA1 mutant BCs (20). It and in vivo revealed the role of c-MYB in different types of is not clear how BRCA1 mutation affects MYB expression, cancer. Classically, we can include leukaemia, colon, breast but several studies indicated BRCA1 as MYB target gene. and adenoid cystic carcinoma in a cohort where MYB is Several putative MYB binding sites were identified in the playing a critical role in cancer initiation and maintenance. BRCA1 promoter (21) and a global chip-on-chip analysis In general, it is believed that high level of MYB expression for MYB binding sites on the promoter also identified is associated with the block in cellular differentiation and BRAC1 as a target gene (22). On the other hand, most of continued proliferation, which leads to the oncogenicity. the BRCA1 tumours are estrogen negative where MYB Overexpression of MYB is observed in all forms of acute expression is suppressed. Therefore, it is possible that myeloid and lymphoid leukaemia and it is associated with mutant BRCA1 forms an alternative transcription complex, poor prognosis. Several studies, including siRNA-based which could activate the expression of other oncogenes gene silencing experiments indicated that MYB expression to maintain the proliferation of tumorigenic cells. Our is essential for the proliferation and the maintenance of studies on cell culture, xenograft model and in mammary leukaemia (12). Most of the cases, this overexpression is a tissue specific knockdown experiments indicated that MYB result of transcription upregulation of MYB which is either is essential for the proliferation of ER+ve BC cell lines driven by a variety of oncoproteins such as MLL-fusion and breast tumour formation (23-25). In ER+ve BC cells, proteins or chromosomal translocations where MYB is expression of MYB is regulated by ligand bound ER-α at the placed in the vicinity of other hyperactive regulatory transcriptional level operated within intron 1. Interestingly, sequences (13). The role of MYB in the maintenance of a steady state expression of MYB was also observed before haematopoietic lineages was not clear until recently, when and after treatment in BC patients resistance to estrogen Sandberg et al. showed that MYB and one of its major synthesis inhibitor aromatase. This unchanged level of coactivators, p300, is required to control the proliferation MYB expression may have a co-relation with the resistance and differentiation of haematopoietic stem and progenitor cases (unpublished). cells (14). Published data from our laboratory also Adenoid cystic carcinoma is a very slow growing established that MYB-p300 interaction plays a very critical rare type of cancer which often metastasizes to lungs, role in the initiation of leukaemia (15). followed by bone and liver. Published data of Persson et al. MYB is essential for the development normal colon, indicated that due to t(6;9) chromosomal translocation, which was established by the fact that MYB depleted MYB very often from a fusion protein with NFIB, which embryos developed with major defect in epithelial a transcription factor. As a result of this translocation, organization of colon (16). Human colon comprises of the last exon (exon 15) of MYB is deleted along with the several millions of the crypt, the functional unit of the 3'-UTR region, which has shown to be responsible for © Annals of Translational Medicine. All rights reserved. atm.amegroups.com Ann Transl Med 2018;6(22):443 Annals of Translational Medicine, Vol 6, No 22 November 2018 Page 3 of 11 the microRNA-based regulation of transcription. High functions. On the other hand, the mechanisms that control expression MYB-NFIB fusion proteins can alter several the synthesis of the transcription factor are often not very MYB target gene expression related to apoptosis, cell well defined or almost impossible to target due to the proliferation/differentiation (26). complexity of the process at multiple levels. The problem A switch between proliferation and differentiation in of targeting the associated epigenetic factors is that the metazoan is maintained by the programmed activity of a cancer cells get multiple epigenetic aberrations and often group of transcription factors [reviewed, Gonda et al. (27)]. develop resistance to the epigenetic drugs (29).
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