TL;DR
The mechanism involved in ERRα recognition of the TMPRSS2-promoter DNA provides insight into ERRα-mediated transcriptional regulation and development of anticancer drugs against ERRα-driven prostate cancer.
The chromosomal translocation t(4;11)(q21;q23) is the most common genetic aberration in KMT2A-rearranged acute leukemia. Although the molecular functions of wild-type KMT2A and AFF1 complexes are well characterized, little is known about the interplay between the reciprocal fusion proteins KMT2A::AFF1 (MA4) and AFF1::KMT2A (A4M). Here, we established model systems to investigate this interplay and the role of the RNA-binding proteins IGF2BP1-3. We also compared the murinized fusion KMT2A::mAff1 (MmA4) with the authentic human KMT2A::AFF1 fusion. Our data indicate that MA4 alone drives aberrantly high expression of only a few target genes, whereas A4M counteracts this detrimental effect. Under these conditions, MA4 induces genes encoding RNA-binding proteins as a counterregulatory response. Both reciprocal fusion transcripts are bound by IGF2BP3, resulting in reduced MA4 protein abundance but increased A4M levels. This effect was not observed for the artificial MmA4 fusion, likely because it cannot recruit the SL-1 complex. Together with previous findings, our results suggest that A4M is crucial through its chromatin-opening activity, which strongly expands the pool of MA4 target genes and thereby promotes the establishment of pre-leukemogenic and leukemogenic gene expression programs.
Background: PRMT5, or protein arginine methyltransferase 5, is recognized as an epigenetic regulator that suppresses gene transcription through symmetric dimethylation of histone arginine residues, including histone H4 arginine 3 (H4R3me2s) and histone H3 arginine 8 (H3R8me2s), modifications associated with chromatin condensation and transcriptional repression. PRMT5-mediated methylation has been associated with recruitment of polycomb repressive complex 2 (PRC2) and enhancer of zeste homolog 2 (EZH2)-mediated H3K27me3 deposition, contributing to stable repression of tumor suppressor genes and apoptosis-related effectors in breast cancer. Methods: The molecular and functional impacts of PRMT5 inhibition were studied in TNBC cell lines with a pharmacological inhibitor (CMP5). Cellular responses were evaluated using a viability assay, qPCR, Western blotting, Annexin V/PI staining, and transwell migration/proliferation assays. Results: PRMT5 inhibition substantially reduced TNBC viability in a time- and dose-dependent manner. EZH2 was downregulated, whereas the tumor suppressor retinoblastoma-like protein 2 (RBL2) was induced, concomitant with low expression of Cyclin D1. These changes were accompanied by upregulation of pro-apoptotic effectors (Caspase-3, Caspase-10, death-associated protein 1 (DAP1), and BCL2-associated x protein (BAX) and repression of the pro-survival B-cell lymphoma 2 (BCL2), consistent with apoptosis-associated molecular responses. Functionally, CMP5 treatment was associated with reduced migratory behavior in TNBC cells under the experimental conditions tested. Conclusions: These findings suggest that PRMT5 inhibition by CMP5 is associated with reduced TNBC cell viability, impaired migration, increased expression of apoptosis-associated regulators and enhanced apoptotic cell death as measured by Annexin V/PI analysis in vitro. Further mechanistic and in vivo studies are required to clarify the therapeutic relevance of PRMT5 inhibition in TNBC.
RNA-binding motif 47 (RBM47), a hub gene in atherosclerosis, induced oxidative stress in macrophages in atherosclerosis progression by enhancing ENC1 stability via binding to the AU-rich elements (AREs). However, RBM47 promoted C-to-U editing of multiple genes, such as acyl-CoA synthetase family member 2 (ACSF2), apoB, CD36, CD170, IL-10, oxysterol binding protein like 9, and transmembrane protein 30a (TMEM30A). These genes play important roles in atherosclerosis. Thus, the role of RBM47 in atherosclerosis may be complex. Notably, ACSF2 and HECT and RLD domain containing E3 ubiquitin protein ligase 2 promoted ferroptosis. TMEM30A exhibited a “don’t eat me” signal. CD170 decreased ADAMTS13 activity. Recombinant ADAMTS-13 was undergoing phase 3 clinical trials. However, the biological significance of these genes after RNA editing, except for apoB and tight junction protein 1, is unclear. RBM47 also stabilized Axin1, Cullin 3, IL-8, Dickkopf WNT signaling pathway inhibitor 1, Kelch-like ECH-associated protein 1, and IL-10 expression by recognizing the GAUSAW (S = G/C, W = A/U) motif and AREs/GU-rich elements (GREs). However, the role of RBM47 in other genes that contain AREs and GREs, such as apoA-II, ABCA1, HMGCR, IFN-γ, IL-15, low-density lipoprotein receptor, oxidized low-density lipoprotein receptor 1, and programmed cell death 1 ligand 1, is unclear. This review focuses on the role and mechanism of RBM47-mediated genes in atherosclerosis to provide knowledge for new targets.
This perspective brings together multiple observations concerning the regulatory architecture and functional interactions of the TP53 gene and its isoforms. The TP53 gene encompasses an internal enhancer-promoter region (P2) located between exons 2 and 5, which is transactivated by full-length TAp53α, to drive the expression of truncated TP53 isoforms ΔN133p53α, β or γ. ΔN133p53α homo-monomers or dimers very likely form hetero-tetramers with homo-dimers of full-length TAp53α. The TAp53α-ΔN133p53 tetramer then acts as a transcription factor augmenting mitochondrial efficiency, DNA repair, telomere restoration and reversing cellular senescence, thus opposing many outputs of tumor suppressive TAp53α homo-tetramers. Other transcription factors, such as estrogen receptor (ER), OCT1, and SOX9 also may bind the P2 promoter-enhancer to promote transcription of oncogenic TP53 isoforms. These transcription factors, together with full-length TAp53α, appear to cooperate to maintain an open chromatin state in the P2 region in a manner reminiscent of a neural "associative memory" network.
Butyrophilin-like 9 (BTNL9), a member of the immunoglobulin superfamily containing a bZIP-like domain, has a poorly defined role in cancer. Here, we identify BTNL9 as a non-canonical transcriptional regulator and investigate its function in non-small cell lung cancer (NSCLC). Coiled-coil prediction, native PAGE, and co-immunoprecipitation demonstrated BTNL9 homodimerization via its bZIP-like region, while subcellular fractionation and immunofluorescence confirmed its presence in both the nucleus and cytoplasm. Chromatin immunoprecipitation sequencing (ChIP-seq) analysis identified 9709 BTNL9-associated genomic regions, including sites proximal to transcription start sites, with enrichment of a cytosine-rich motif. Whether chromatin association reflects direct DNA binding or indirect co-regulatory interaction remains to be experimentally confirmed. Integrated transcriptomic and protein analyses revealed that BTNL9 overexpression represses genes involved in cell cycle progression and DNA replication while activating a subset of p53-associated pathways. Consistently, functional assays showed that increased BTNL9 expression induces cell cycle arrest, suppresses proliferation and clonogenicity, and inhibits tumor growth in xenograft models. In addition, cytotoxicity assays demonstrated enhanced sensitivity to bortezomib, with context-dependent effects on etoposide response. Analysis of public clinical datasets further showed that low BTNL9 expression is associated with advanced tumor stage, reduced remission rates, and poorer survival outcomes in NSCLC. These findings identify BTNL9 as a non-canonical tumor-suppressive transcriptional regulator with potential biomarker relevance in NSCLC.