Transcription regulation of MYB: a potential and novel therapeutic target in cancer

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; P-TEFb complex; transcriptional regulation.

Figure 1

MLL-fusion protein driven transcription of c-MYB. The transcriptionally active super elongation complex is formed when MLL-fusion proteins recruits several proteins along with the core protein complex WARD. Th process initiates with the modulation of the chromosomal three-dimensional structure that brings the enhancer close to the proximal region of the promoter followed by the accumulation of the MLL-fusion protein and other co-factors to form the SEC. Phosphorylation of the CTD of PolII, the penultimate stage of this process, is triggered by the recruitment of the P-TEFb complex by BRD4. CTD, C-terminal domain; SEC, super elongation complex.

Figure 2

Regulation of transcription of C-MYB in estrogen positive breast cancer. In the absence of estrogen transcription pauses at the 1.7 kb downstream of the transcription start site and generates short transcripts and a stem-loop structure followed by a polyT trail upon transcription (upper panel). In the presence of estrogen, the ER’s binds to the upstream of the 72 bp regulatory elements and form a regulatory complex includes P-TEFb. Phosphorylation of the ser-2 residues at the CTD of RNA PolII drives transcription past the pausing site till to the end of the gene. CTD, C-terminal domain; ER, estrogen receptor.

Figure 3

Transcriptional regulation of C-MYB in colon cancer cells. Transcription of the C-MYB depends upon the length of the polyT trail and the stem-loop structure that forms during transcription. The heterodimeric NF-κB p50 binds to the nascent stem-loop RNA forms upon transcription through its p50 subunit and recruits the P-TEFb complex by interacting with its p65 subunit. Multiprotein complex formed by NF-κB-PTEFb functions as a major driver of the transcription.