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The protooncogene MYC regulates a variety of cellular processes, including proliferation and metabolism. Maintaining MYC at homeostatic levels is critical to normal cell function; overexpression drives many cancers. MYC stability is regulated through phosphorylation: phosphorylation at Thr58 signals degradation while Ser62 phosphorylation leads to its stabilization and functional activation. The bromodomain protein 4 (BRD4) is a transcriptional and epigenetic regulator with intrinsic kinase and histone acetyltransferase (HAT) activities that activates transcription of key protooncogenes, including MYC. We report that BRD4 phosphorylates MYC at Thr58, leading to MYC ubiquitination and degradation, thereby regulating MYC target genes. Importantly, BRD4 degradation, but not inhibition, results in increased levels of MYC protein. Conversely, MYC inhibits BRD4’s HAT activity, suggesting that MYC regulates its own transcription by limiting BRD4-mediated chromatin remodeling of its locus. The MYC stabilizing kinase, ERK1, regulates MYC levels directly and indirectly by inhibiting BRD4 kinase activity. These findings demonstrate that BRD4 negatively regulates MYC levels, which is counteracted by ERK1 activation.

The bromodomain and extraterminal (BET) domain family of proteins binds to acetylated lysines on histones and regulates gene transcription. Recently, BET inhibitors (BETi) have been developed that show promise as potent anticancer drugs against various solid and hematological malignancies. Here we show that the structurally novel and orally bioavailable BET inhibitor RVX2135 inhibits proliferation and induces apoptosis of lymphoma cells arising in Myc-transgenic mice in vitro and in vivo. We find that BET inhibition exhibits broad transcriptional effects in Myc-transgenic lymphoma cells affecting many transcription factor networks. By examining the genes induced by BETi, which have largely been ignored to date, we discovered that these were similar to those induced by histone deacetylase inhibitors (HDACi). HDACi also induced cell-cycle arrest and cell death of Myc-induced murine lymphoma cells and synergized with BETi. Our data suggest that BETi sensitize Myc-overexpressing lymphoma cells partly by inducing HDAC-silenced genes, and suggest synergistic and therapeutic combinations by targeting the genetic link between BETi and HDACi.

BRD4, member of the Bromodomain and Extraterminal (BET) protein family, is largely acknowledged in cancer for its role in super-enhancers (SEs) organization and oncogenes expression regulation. Inhibition of BRD4 shortcuts the communication between SEs and target promoters with a subsequent cell-specific repression of oncogenes to which cancer cells are addicted and cell death. To date, this is the most credited mechanism of action of BET inhibitors, a class of small molecules targeting BET proteins which are currently in clinical trials in several cancer settings. However, recent evidence indicates that BRD4 relevance in cancer goes beyond its role in transcription regulation and identifies this protein as a keeper of genome stability. Indeed, a non-transcriptional role of BRD4 in controlling DNA damage checkpoint activation and repair as well as telomere maintenance has been proposed, throwing new lights into the multiple functions of this protein and opening new perspectives on the use of BETi in cancer. Here we discuss the current available information on non-canonical, non-transcriptional functions of BRD4 and on their implications in cancer biology. Integrating this information with the already known BRD4 role in gene expression regulation, we propose a “common” model to explain BRD4 genomic function. Furthermore, in light of the transversal function of BRD4, we provide new interpretation for the cytotoxic activity of BETi and we discuss new possibilities for a wide and focused employment of these drugs in clinical settings.

Prostate cancer has the second highest incidence among cancers in men worldwide and is the second leading cause of cancer deaths of men in the United States. Although androgen deprivation can initially lead to remission, the disease often progresses to castration-resistant prostate cancer (CRPC), which is still reliant on androgen receptor (AR) signaling and is associated with a poor prognosis. Some success against CRPC has been achieved by drugs that target AR signaling, but secondary resistance invariably emerges, and new therapies are urgently needed. Recently, inhibitors of bromodomain and extraterminal (BET) family proteins have shown growth-inhibitory activity in preclinical models of CRPC. Here, we demonstrate that ARV-771, a small-molecule pan-BET degrader based on proteolysis-targeting chimera (PROTAC) technology, demonstrates dramatically improved efficacy in cellular models of CRPC as compared with BET inhibition. Unlike BET inhibitors, ARV-771 results in suppression of both AR signaling and AR levels and leads to tumor regression in a CRPC mouse xenograft model. This study is, to our knowledge, the first to demonstrate efficacy with a small-molecule BET degrader in a solid-tumor malignancy and potentially represents an important therapeutic advance in the treatment of CRPC.

Background Exosomes have emerged as vital biomarkers of multiple cancers and contain abundant circular RNAs (circRNAs). However, the potential for exosomal circRNAs to be used in diagnostics and their molecular mechanism of action in colorectal cancer (CRC) remain unclear. Methods CRC-specific exosomal circRNAs were identified by RNA sequencing, exoRBase database and a tissue microarray. The diagnostic performance of plasma exosomal circRNAs was evaluated among cancer-free controls, precancer individuals, CRC patients, and patients with other types of cancer. The corresponding biological functions were mainly assessed using circRNA pull-down, proteomic analysis, and RNA immunoprecipitation assay underlying cellular and mouse models. Results CircLPAR1 was encapsulated in exosomes with high stability and detectability, and its expression in plasma exosomes was remarkably decreased during CRC development but recovered after surgery. Exosomal circLPAR1 showed cancer specificity in CRC diagnosis and increased the diagnostic performance to an area under the receiver operating characteristic curve of 0.875, as determined by analysing its performance in combination with common clinical biomarkers CEA and CA19–9. Additionally, circLPAR1 was downregulated in CRC tissues and was associated with overall survival. Mechanistically, exosomal circLPAR1 was internalized by CRC cells, and it suppressed tumor growth, likely because exosomal circLPAR1 directly bound with eIF3h specifically suppressed the METTL3-eIF3h interaction, decreasing the translation of oncogene BRD4 . Conclusions This comprehensive study highlights plasma exosomal circLPAR1 as a promising predictor in CRC diagnosis and describes its biological regulation of colorectal tumorigenesis. This study provides a new perspective on early diagnosis in the clinic and pathogenesis in disease development.

Double/triple-hit lymphomas (DHL/THL) account for 5–10% of diffuse large B cell lymphoma (DLBCL) with rearrangement of MYC and BCL2 and/or BCL6 resulting in MYC overexpression. Despite the poor prognosis of DHL, R-CHOP chemotherapy remains the treatment backbone and new targeted therapy is needed. We performed comprehensive cytogenetic studies/fluorescence in situ hybridization on DLBCL and Burkitt lymphoma cell lines ( n = 11) to identify the DHL/THL DLBCL in vitro model. We identified MYC/IG in Raji and Ramos (single hit); MYC/IG-BCL2 (DHL) in DOHH2, OCI-LY1, SUDHL2, and OCI-LY10; MYC/IG-BCL2/BCL6 (THL) in VAL; and no MYC rearrangement in U2932 and HBL1 (WT-MYC). Targeting MYC in the DHL/THL DLBCLs through bromodomain extra-terminal inhibitors (BETi) (JQ1, I-BET, and OTX015) significantly ( p < 0.05) reduced proliferation, similar to WT-MYC cells, accompanied by decreased MYC but not BCL2 protein. Moreover, BETi suppressed MYC transcription and decreased BRD4 binding to MYC promoter in DHL cells. CD47 and PD-L1 are immunoregulatory molecules often expressed on tumors and regulated by MYC . High levels of surface CD47 but not surface PD-L1 was observed in DHL/THL, which was reduced by JQ1 treatment. BETi in combination with Pan-HDAC inhibitor had a limited effect on survival of DHL/THL, while combination of BETi and BCL2 inhibitor (ABT-199) had a significant ( p < 0.005) inhibitory effect on survival followed by BCL-XL inhibition. Overall, the data suggests that MYC-expressing DLBCLs are probably addicted to the MYC-oncogenic effect regardless of MYC rearrangements. In summary, we identified an in vitro model for DHL/THL DLBCLs and provide evidence for the therapeutic potential of BET inhibitor alone or in combination with BCL2 inhibitor.

[This corrects the article DOI: 10.3389/fphar.2021.664176.].[This corrects the article DOI: 10.3389/fphar.2021.664176.].

BRD4 is well known for its role in super-enhancer organization and transcription activation of several prominent oncogenes including c-MYC and BCL2. As such, BRD4 inhibitors are being pursued as promising therapeutics for cancer treatment. However, drug resistance also occurs for BRD4-targeted therapies. Here, we report that BRD4 unexpectedly interacts with the LSD1/NuRD complex and colocalizes with this repressive complex on super-enhancers. Integrative genomic and epigenomic analyses indicate that the BRD4/LSD1/NuRD complex restricts the hyperactivation of a cluster of genes that are functionally linked to drug resistance. Intriguingly, treatment of breast cancer cells with a small-molecule inhibitor of BRD4, JQ1, results in no immediate activation of the drug-resistant genes, but long-time treatment or destabilization of LSD1 by PELI1 decommissions the BRD4/LSD1/NuRD complex, leading to resistance to JQ1 as well as to a broad spectrum of therapeutic compounds. Consistently, PELI1 is up-regulated in breast carcinomas, its level is negatively correlated with that of LSD1, and the expression level of the BRD4/LSD1/NuRD complex–restricted genes is strongly correlated with a worse overall survival of breast cancer patients. Together, our study uncovers a functional duality of BRD4 in superenhancer organization of transcription activation and repression linking to oncogenesis and chemoresistance, respectively, supporting the pursuit of a combined targeting of BRD4 and PELI1 in effective treatment of breast cancer.

Liver fibrosis is characterized by the persistent deposition of extracellular matrix components by hepatic stellate cell (HSC)-derived myofibroblasts. It is the histological manifestation of progressive, but reversible wound-healing processes. An unabated fibrotic response results in chronic liver disease and cirrhosis, a pathological precursor of hepatocellular carcinoma. We report here that JQ1, a small molecule inhibitor of bromodomain-containing protein 4 (BRD4), a member of bromodomain and extraterminal (BET) proteins, abrogate cytokine-induced activation of HSCs. Cistromic analyses reveal that BRD4 is highly enriched at enhancers associated with genes involved in multiple profibrotic pathways, where BRD4 is colocalized with profibrotic transcription factors. Furthermore, we show that JQ1 is not only protective, but can reverse the fibrotic response in carbon tetrachloride-induced fibrosis in mouse models. Our results implicate that BRD4 can act as a global genomic regulator to direct the fibrotic response through its coordinated regulation of myofibroblast transcription. This suggests BRD4 as a potential therapeutic target for patients with fibrotic complications.

Angiogenesis dysregulation contributes to inflammation, infections, immune disorders, and carcinogenesis. Bromodomain-containing protein 4 (BRD4) is an epigenetic reader that recognizes histone proteins and acts as a transcriptional regulator to trigger tumor growth and the inflammatory response. The pan-bromodomain and extra-terminal domain (BET) inhibitor, (+)-JQ1 ( 1 ), was reported to inhibit angiogenesis. However, owing to the non-selectivity action of (+)-JQ1 towards all BET family members, the role of BRD4 and that of its bromodomains (BD1 and BD2) in angiogenesis remains elusive. Herein, we identified a potent BRD4 inhibitor, ZL0513 ( 7 ), which exhibited significant anti-angiogenic effects in chick embryo chorioallantoic membrane (CAM) and yolk sac membrane (YSM) models. This inhibitor also directly suppressed the viability and tube formation of human umbilical vascular endothelial cells (HUVECs). Moreover, ZL0513 ( 7 ) was found to inhibit the phosphorylation of c-jun and c-fos, important members of activating protein-1 (AP-1) transcription factor complexes that enhance angiogenesis. The findings on this novel BRD4 inhibitor indicate that, in addition to being a powerful pharmacological tool for further elucidating the roles and functions of BRD4 and its BD domains in angiogenesis, it may serve as a potential therapeutic strategy for targeting the vasculature in various angiogenesis-dysregulated human diseases.