JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

Handoko, Lusy; Kaczkowski, Bogumił; Hon, Chung-Chau; Lizio, Marina; Wakamori, Masatoshi; Matsuda, Takayoshi; Ito, Takuhiro; Jeyamohan, Prashanti; Sato, Yuko; Sakamoto, Kensaku; Yokoyama, Shigeyuki; Kimurâ, Hiroshi; Minoda, Aki; Umehara, Takashi

doi:10.1080/15592294.2018.1469891

Cited by 34 publications

(25 citation statements)

References 73 publications

(107 reference statements)

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“…Different from the majority of the previously reported proteins encoded by the BET-regulated genes 1,7,27,29 , IDO1 mediates metabolic immune escape in cancer 26 . This enzyme by its catalytic activity converts tryptophan into l -kynurenine.…”

Section: Discussioncontrasting

confidence: 75%

“…The BET family proteins are the epigenetic readers that regulate the expression of genes including those encoding transcription factors and other proteins 1,27 . A general mode of the BET proteins including BRD2, BRD3, and BRD4 to regulate gene transcription is by co-occupying the acetylated histones at the promoters of their target genes and Pol II, and by removing such occupation, BET inhibitors inhibit gene transcription 27 . Data have consistently shown that BRD2, BRD3, and BRD4 directly bind to the acetylated H3K27 sites at the promoter of IDO1 and Pol II.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of the BET family reduces its new target gene IDO1 expression and the production of l-kynurenine

Tian

Chen

et al. 2019

Cell Death Dis

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The bromodomain and extra terminal domain (BET) family members, including BRD2, BRD3, and BRD4, act as epigenetic readers to regulate gene expression. Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme that participates in tumor immune escape primarily by catalyzing tryptophan to l -kynurenine. Here, we report that IDO1 is a new target gene of the BET family. RNA profiling showed that compound 9, a new BET inhibitor, reduced IDO1 mRNA up to seven times in Ty-82 cells. IDO1 differentially expressed in tumor cells and its expression could be induced with interferon gamma (IFN-γ). BET inhibitors (ABBV-075, JQ1, and OTX015) inhibited both constitutive and IFN-γ-inducible expression of IDO1 . Similarly, reduction of BRD2, BRD3, or BRD4 decreased IDO1 expression. All these BET family members bound to the IDO1 promoter via the acetylated histone H3. JQ1 led to their release and reduced enrichment of RNA polymerase II (Pol II) on the promoter. IFN-γ increased the binding of BRD2, BRD3, BRD4, and Pol II on the IDO1 promoter by increasing the acetylation of histone H3, which could be prevented by JQ1 partially or even completely. Furthermore, both JQ1 and OTX015 decreased the production of l -kynurenine. The combination of BET inhibitors with the IDO1 inhibitor further reduced l -kynurenine, though only marginally. Importantly, the BET inhibitor ABBV-075 significantly inhibited the growth of human Ty-82 xenografts in nude mice and reduced both protein and mRNA levels of IDO1 in the xenografts. This finding lays a basis for the potential combination of BET inhibitors and IDO1 inhibitors for the treatment of IDO1-expressing cancers.

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Section: Discussioncontrasting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Inhibition of the BET family reduces its new target gene IDO1 expression and the production of l-kynurenine

Tian

Chen

et al. 2019

Cell Death Dis

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“…The H3K4me3 mark is also associated with open centromeres H3K4me3 59 where Z-DNA hotspots were found in ChAP-seq experiment, and our DeepZ model confirmed it too. Our model selected enhancer H3K27ac and negatively selected superenhancer mark H4K5K8ac 60 . The other two marks H3K27me3 and H2A.ZK4K7K11ac are mostly associated with gene deregulation by chromatin remodeling, though the last has many controversial functions 61 .…”

Section: Resultsmentioning

confidence: 99%

Deep learning approach for predicting functional Z-DNA regions using omics data

Beknazarov

Jin

Poptsova

2020

Sci Rep

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Computational methods to predict Z-DNA regions are in high demand to understand the functional role of Z-DNA. The previous state-of-the-art method Z-Hunt is based on statistical mechanical and energy considerations about B- to Z-DNA transition using sequence information. Z-DNA CHiP-seq experiment results showed little overlap with Z-Hunt predictions implying that sequence information only is not sufficient to explain emergence of Z-DNA at different genomic locations. Adding epigenetic and other functional genomic mark-ups to DNA sequence level can help revealing the functional Z-DNA sites. Here we take advantage of the deep learning approach that can analyze and extract information from large volumes of molecular biology data. We developed a machine learning approach DeepZ that aggregates information from genome-wide maps of epigenetic markers, transcription factor and RNA polymerase binding sites, and chromosome accessibility maps. With the developed model we not only verify the experimental Z-DNA predictions, but also generate the whole-genome annotation, introducing new possible Z-DNA regions, which have not yet been found in experiments and can be of interest to the researchers from various fields.

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“…However, several recent reports suggested that JQ1 may also have unexpected effects. JQ1 affects both BET proteindependent and -independent transcription regulation and regulates distinct pathways upon continued treatment (14). JQ1 also induces variable oncogenic pathway responses in ovarian cancer cells (15).…”

Section: Introductionmentioning

confidence: 99%

Small molecule JQ1 promotes prostate cancer invasion via BET-independent inactivation of FOXA1

Wang¹,

Xu²,

Kao³

et al. 2020

Journal of Clinical Investigation

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Recent findings have shown that inhibitors targeting bromodomain and extraterminal domain (BET) proteins, such as the small molecule JQ1, are potent growth inhibitors of many cancers and hold promise for cancer therapy. However, some reports have also revealed that JQ1 can activate additional oncogenic pathways and may affect epithelial-to-mesenchymal transition (EMT). Therefore, it is important to address the potential unexpected effect of JQ1 treatment, such as cell invasion and metastasis. Here, we showed that in prostate cancer, JQ1 inhibited cancer cell growth but promoted invasion and metastasis in a BET protein-independent manner. Multiple invasion pathways including EMT, bone morphogenetic protein (BMP) signaling, chemokine signaling, and focal adhesion were activated by JQ1 to promote invasion. Notably, JQ1 induced upregulation of invasion genes through inhibition of Forkhead box protein A1 (FOXA1), an invasion suppressor in prostate cancer. JQ1 directly interacted with FOXA1 and inactivated FOXA1 binding to its interacting repressors TLE3, HDAC7, and NFIC, thereby blocking FOXA1-repressive function and activating the invasion genes. Our findings indicate that JQ1 has an unexpected effect of promoting invasion in prostate cancer. Thus, the ill effect of JQ1 or its derived therapeutic agents cannot be ignored during cancer treatment, especially in FOXA1-related cancers.

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JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

Cited by 34 publications

References 73 publications

Inhibition of the BET family reduces its new target gene IDO1 expression and the production of l-kynurenine

Inhibition of the BET family reduces its new target gene IDO1 expression and the production of l-kynurenine

Deep learning approach for predicting functional Z-DNA regions using omics data

Small molecule JQ1 promotes prostate cancer invasion via BET-independent inactivation of FOXA1

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