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Role of the Mediator Complex and MicroRNAs in Breast Cancer Etiology - PubMed

  • ️Sat Jan 01 2022

Review

Role of the Mediator Complex and MicroRNAs in Breast Cancer Etiology

Edio Maldonado et al. Genes (Basel). 2022.

Abstract

Transcriptional coactivators play a key role in RNA polymerase II transcription and gene regulation. One of the most important transcriptional coactivators is the Mediator (MED) complex, which is an evolutionary conserved large multiprotein complex. MED transduces the signal between DNA-bound transcriptional activators (gene-specific transcription factors) to the RNA polymerase II transcription machinery to activate transcription. It is known that MED plays an essential role in ER-mediated gene expression mainly through the MED1 subunit, since estrogen receptor (ER) can interact with MED1 by specific protein-protein interactions; therefore, MED1 plays a fundamental role in ER-positive breast cancer (BC) etiology. Additionally, other MED subunits also play a role in BC etiology. On the other hand, microRNAs (miRNAs) are a family of small non-coding RNAs, which can regulate gene expression at the post-transcriptional level by binding in a sequence-specific fashion at the 3' UTR of the messenger RNA. The miRNAs are also important factors that influence oncogenic signaling in BC by acting as both tumor suppressors and oncogenes. Moreover, miRNAs are involved in endocrine therapy resistance of BC, specifically to tamoxifen, a drug that is used to target ER signaling. In metazoans, very little is known about the transcriptional regulation of miRNA by the MED complex and less about the transcriptional regulation of miRNAs involved in BC initiation and progression. Recently, it has been shown that MED1 is able to regulate the transcription of the ER-dependent miR-191/425 cluster promoting BC cell proliferation and migration. In this review, we will discuss the role of MED1 transcriptional coactivator in the etiology of BC and in endocrine therapy-resistance of BC and also the contribution of other MED subunits to BC development, progression and metastasis. Lastly, we identified miRNAs that potentially can regulate the expression of MED subunits.

Keywords: MED1 coactivator; MED12 coactivator; breast cancer; miRNA regulation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1

Schematic representation of the human Estrogen Receptor alpha. The NTD domain (N-terminal domain, red, (A/B)) contains the sub-domains (A,B), which are essential for transcriptional activation. DBD domain (DNA-binding domain, green, (C)) is the specific DNA-binding domain, which binds to the ERE in the gene promoter of ER-target genes. The H region is the flexible hinge domain (blue, (D)). LBD domain (ligand binding domain, yellow, (E)) is the specific estrogen binding site, and is required for receptor dimerization, nuclear localization, and transcriptional coactivators/corepressors recruitment. (F) domain (white) seems to perform a similar function as the NTD domain. The numbers indicate the amino acid residue positions in the ER.

Figure 2
Figure 2

A mechanism to explain the tamoxifen-resistance in ER-positive HER2-expressing BC. Under normal cellular conditions, the estrogens (E) can bind to the ER and activate gene expression of ER-target genes (gene on). In those ER-positive BC, the tamoxifen (T) binds to the ER and produces a conformational change that results in the recruitment of transcriptional co-repressors (SMRT and N-CoR) which block gene expression (gene off) of ER-target genes, and it produces a tamoxifen-sensitive BC. However, in the presence of HER2 receptor, the ER receptor bound to tamoxifen (T), recruits MED1 co-activator, which is heavily phosphorylated by MAPK kinases (activated by HER2) producing an activation of those ER-target genes (gene on) and the BC becomes tamoxifen-resistant. MAPK kinases phosphorylate MED1 at T residues in position 1032 and 1457. TATA is the DNA-binding sequence of TBP factor in the gene promoter. RNAPII is the RNA polymerase II enzyme which transcribes. MED is the Mediator complex. GTFs are the auxiliary factors for RNAPII and ERE is the estrogen response element.

Figure 3
Figure 3

Schematic overview of the modular structure of the mammalian Mediator complex based on recent evidence derived from electron microscopy data. The Mediator consists of almost thirty polypeptides organized in three modules, which are Tail (red), Middle (green) and Head (cyan), which are held together by MED14. The Head and Middle modules constitute the essential core that is necessary for transcription regulation, whereas the Tail and the CDK8 kinase modules perform regulatory functions. The kinase module (yellow) consists of MED12, MED13 and the CCNC-CDK8 pair. This module associates to the Mediator after cell signaling and is able to repress transcription. CCNC-CDK8 pair can interact with MED12, and this polypeptide interacts with MED13, which tethers the Kinase module to the Mediator by interacting mainly with MED26 and MED1 of the Middle module. Modified from reference [41].

Figure 4
Figure 4

Structural domain organization of MED1 and MED12 proteins. (A) MED1 is a 1581 amino acids long polypeptide, which contains functional domains to perform its coactivator function. The MED1 domain (yellow, 60–427) is conserved in MED1 proteins from all eukaryotes. The NR-boxes or LxxLL motifs locate at positions 604 (LTSLL) and 645 (LMNLL) and they serve as protein–protein interaction motifs for nuclear receptors, such as ER. A Ser-Rich domain is located at the C-terminus of the polypeptide (orange, 1078–1283). Two residues (T1032) and (T1457) are phosphorylated by MAPK, an event that increases the activity of MED1, (B) The N-terminal region contains the CCNC-CDK8 binding and activation domain (1–50) and contains also a MED1 conserved region (yellow, 103–162). Two overlapping NR-boxes (272–281; LLKLLPLL), which are nuclear receptor binding LxxLL motifs. A MED12-LCEWAV domain (green, 286–757) is present in the polypeptide, which is unknown yet. At the C-terminus contains a Proline-Glutamine-Leucine (orange, 1818–2020; MED12-PQL), which binds effector molecules. At the C-terminal end of the polypeptide is located the odd-paired domain (black, 2250–2177; OPA), which also binds effector molecules.

Figure 5
Figure 5

A model to explain the interplay of the ER-MED1-miR-191/425 in BC. The estrogen (E) binds to the estrogen receptor (ER) and translocate to the nucleus, where it can bind to the estrogen receptor element (ERE) in the gene promoter region of the miR-191/425 gene to activate its expression. MED1 is recruited to the promoter by interactions with the ER and serves as a bridge between promoter-bound ER and the general transcription factors (GTFs)/pol II transcription machinery. The expressed miR-191/425 regulates downstream target genes as indicated.

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