Cytotoxic activity of bromodomain inhibitor NVS-CECR2-1 on human cancer cells

Park, Seul Gi; Lee, Daye; Seo, Hye-Ran; Lee, Shin Ai; Kwon, Jongbum

doi:10.1038/s41598-020-73500-7

Cited by 17 publications

(9 citation statements)

References 29 publications

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“…The bromodomain of CECR2 was predicted to be highly druggable ( 27 ). Two highly potent and specific CECR2 inhibitors, GNE-886 and NVS-CECR2-1, have been developed by Genentech ( 28 ) and the joint effort of Structural Genomics Consortium (SGC) and Novartis ( 29 ), respectively. However, the specific functions of CECR2 in cancer, especially in metastasis, remain unclear.…”

Section: Introductionmentioning

confidence: 99%

CECR2 drives breast cancer metastasis by promoting NF-κB signaling and macrophage-mediated immune suppression

et al. 2022

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Metastasis is the major cause of cancer-related deaths due to the lack of effective therapies. Emerging evidence suggests that certain epigenetic and transcriptional regulators drive cancer metastasis and could be targeted for metastasis treatment. To identify epigenetic regulators of breast cancer metastasis, we profiled the transcriptomes of matched pairs of primary breast tumors and metastases from human patients. We found that distant metastases are more immune inert with increased M2 macrophages compared to their matched primary tumors. The acetyl-lysine reader, cat eye syndrome chromosome region candidate 2 (CECR2), was the top up-regulated epigenetic regulator in metastases associated with an increased abundance of M2 macrophages and worse metastasis-free survival. CECR2 was required for breast cancer metastasis in multiple mouse models, with more profound effect in the immunocompetent setting. Mechanistically, the nuclear factor κB (NF-κB) family member v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA) recruits CECR2 to increase chromatin accessibility and activate the expression of their target genes. These target genes include multiple metastasis-promoting genes, such as TNC , MMP2 , and VEGFA , and cytokine genes CSF1 and CXCL1 , which are critical for immunosuppression at metastatic sites. Consistent with these results, pharmacological inhibition of CECR2 bromodomain impeded NF-κB–mediated immune suppression by macrophages and inhibited breast cancer metastasis. These results reveal that targeting CECR2 may be a strategy to treat metastatic breast cancer.

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Section: Introductionmentioning

confidence: 99%

CECR2 drives breast cancer metastasis by promoting NF-κB signaling and macrophage-mediated immune suppression

et al. 2022

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“…For instance, non-BET family inhibitor NVS-CECR2-1 inhibits chromatin binding of CECR2 BRD and displaces CECR2 from chromatin within cells. NVS-CECR2-1 exhibits cytotoxic activity against various human cancer cells, killing SW48 colon cancer cells by inducing apoptosis [ 48 ]. In melanoma, the iBRD9 (TP-472) blocked tumor growth by suppressing ECM-mediated oncogenic signaling and inducing apoptosis [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

The Functional Role and Regulatory Mechanism of Bromodomain-Containing Protein 9 in Human Uterine Leiomyosarcoma

Yang

Bariani

Falahati

et al. 2022

Cells

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Uterine leiomyosarcoma (uLMS) is the most common type of uterine sarcoma associated with poor prognosis, high rates of recurrence, and metastasis. There is currently limited information about uLMS molecular mechanisms of origin and development. Bromodomain (BRD)-containing proteins are involved in many biological processes, most notably epigenetic regulation of transcription, and BRD protein dysfunction has been linked to many diseases including tumorigenesis. However, the role of BRD proteins in the pathogenesis of uLMS is unknown. Here, we show for the first time that BRD9 is aberrantly overexpressed in uLMS tissues compared to adjacent myometrium. BRD9 expression is also upregulated in uLMS cell lines compared to benign uterine fibroid and myometrium cell lines. Inhibition of BRD9 using the specific inhibitor (TP-472) suppressed uLMS cell proliferation via inducing apoptosis and cell cycle arrest. To further characterize the mechanistic basis for TP-472 inhibition of uLMS cell growth, we performed a comparative RNA-seq analysis of vehicle-treated and TP-472-treated uLMS cells (n = 4 each). Bioinformatics analysis revealed that TP-472 treatment distinctly altered the uLMS cell transcriptome. Gene set enrichment analysis identified critical pathways altered by BRD9 inhibition, including interferon-alpha response, KRAS signaling, MYC targets, TNF-a signaling via NFkB, and MTORC1 signaling. Parsimonious gene correlation network analysis identified nine enriched modules, including cell cycle and apoptosis modules. Moreover, the ENCODE Histone Modifications gene set and TargetScan microRNA analysis in Enrichr suggested that TP-472-induced BRD9 inhibition may alter the uLMS cell transcriptome by reprograming the oncogenic epigenome and inducing miRNA-mediated gene regulation. Therefore, BRD9 constitutes a specific vulnerability in malignant uLMS, and targeting non-BET BRD proteins in uLMS may provide a promising and novel strategy for treating patients with this aggressive uterine cancer.

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“…The salt gradient chromatin fractionation was performed as previously described ( Park et al, 2020 ). Briefly, cells were lysed in CEBN buffer (10 mM HEPES [pH 7.8], 10 mM KCl, 1.5 mM MgCl2, 0.34 M sucrose, 10% glycerol, 0.2% NP-40, protease inhibitors as described above) and centrifuged to separate supernatant (cytoplasmic fraction) from pellet.…”

Section: Methodsmentioning

confidence: 99%

CHIP and BAP1 Act in Concert to Regulate INO80 Ubiquitination and Stability for DNA Replication

Seo

Jeong

Lee

et al. 2021

Molecules and Cells

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The INO80 chromatin remodeling complex has roles in many essential cellular processes, including DNA replication. However, the mechanisms that regulate INO80 in these processes remain largely unknown. We previously reported that the stability of Ino80, the catalytic ATPase subunit of INO80, is regulated by the ubiquitin proteasome system and that BRCA1-associated protein-1 (BAP1), a nuclear deubiquitinase with tumor suppressor activity, stabilizes Ino80 via deubiquitination and promotes replication fork progression. However, the E3 ubiquitin ligase that targets Ino80 for proteasomal degradation was unknown. Here, we identified the C-terminus of Hsp70-interacting protein (CHIP), the E3 ubiquitin ligase that functions in cooperation with Hsp70, as an Ino80-interacting protein. CHIP polyubiquitinates Ino80 in a manner dependent on Hsp70. Contrary to our expectation that CHIP degrades Ino80, CHIP instead stabilizes Ino80 by extending its half-life. The data suggest that CHIP stabilizes Ino80 by inhibiting degradative ubiquitination. We also show that CHIP works together with BAP1 to enhance the stabilization of Ino80, leading to its chromatin binding. Interestingly, both depletion and overexpression of CHIP compromise replication fork progression with little effect on fork stalling, as similarly observed for BAP1 and Ino80, indicating that an optimal cellular level of Ino80 is important for replication fork speed but not for replication stress suppression. This work therefore idenitifes CHIP as an E3 ubiquitin ligase that stabilizes Ino80 via nondegradative ubiquitination and suggests that CHIP and BAP1 act in concert to regulate Ino80 ubiquitination to fine-tune its stability for efficient DNA replication.

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Cytotoxic activity of bromodomain inhibitor NVS-CECR2-1 on human cancer cells

Cited by 17 publications

References 29 publications

CECR2 drives breast cancer metastasis by promoting NF-κB signaling and macrophage-mediated immune suppression

CECR2 drives breast cancer metastasis by promoting NF-κB signaling and macrophage-mediated immune suppression

The Functional Role and Regulatory Mechanism of Bromodomain-Containing Protein 9 in Human Uterine Leiomyosarcoma

CHIP and BAP1 Act in Concert to Regulate INO80 Ubiquitination and Stability for DNA Replication

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