JQ1, an inhibitor of the epigenetic reader BRD4, suppresses the bidirectional MYC-AP4 axis via multiple mechanisms

Choi, Sung Kyung; Hong, Seong Hwi; Kim, Hyuk Soon; Shin, Chan Young; Nam, Suk Woo; Choi, Wahn Soo; Han, Jeung Whan; You, Jueng Soo

doi:10.3892/or.2015.4410

Cited by 22 publications

(24 citation statements)

References 29 publications

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“…JQ1, a BET bromodomain inhibitor, has been shown to target the epigenetic “reader” thereby playing critical roles in transcriptional elongation and cell cycle regulation [Kanno et al, ]. In addition, JQ1 has been demonstrated to exert anti‐cancer effects both in vitro and in vivo via c‐Myc‐dependent and c‐Myc‐independent manners [Lee et al, ; Choi et al, ]. In this connection, we here demonstrated that JQ1 inhibits the growth of chondrosarcoma cells by the induction of G0/G1 cell cycle arrest, cell senescence, and apoptosis.…”

Section: Discussionsupporting

confidence: 68%

The BET Bromodomain Inhibitor JQ1 Suppresses Chondrosarcoma Cell Growth via Regulation of YAP/p21/c-Myc Signaling

et al. 2017

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Chondrosarcoma, the second-most frequent primary bone malignancy, is generally more resistant to conventional chemotherapy and radiotherapy. Therefore, the development of an effective adjuvant therapy is necessary. Recently, targeting the epigenetic regulator such as bromodomain and extraterminal domain (BET) proteins has achieved great success. For instance, the bromodomain inhibitor JQ1 has been shown to inhibit the growth of several cancer cells both in vitro and in vivo. Herein, we demonstrated that JQ1 significantly inhibited chondrosarcoma cell growth and colony formation. JQ1 also induced marked G1-phase cell cycle arrest coincided with the up-regulation of p21 , p27 , and Cyclin D1 expression, and the down-regulation of Cyclin E2 expression. Moreover, JQ1 induced the premature senescence of SW 1353 cells, and that prolong treatment of JQ1 caused cell apoptosis. Mechanistically, the JQ1-induced cell growth inhibition was correlated with the suppression of c-Myc and Bcl-xL, which are the prime genes for cell cycle control and anti-apoptosis. Furthermore, we demonstrated that p21 negatively regulated the expression of c-Myc and Bcl-xL upon JQ1 treatment, and that the growth inhibition of SW 1353 and Hs 819.T cells and induction of p21 were predominantly regulated by the LATS1/YAP signaling but not through a p53-dependent manner. In conclusion, we disclosed a novel mechanism that JQ1 inhibits cell proliferation, induces cell senescence and apoptosis of chondrosarcoma cells through the regulation of the YAP/p21/c-Myc/Bcl-xL signaling axis. J. Cell. Biochem. 118: 2182-2192, 2017. © 2017 Wiley Periodicals, Inc.

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Section: Discussionsupporting

confidence: 68%

The BET Bromodomain Inhibitor JQ1 Suppresses Chondrosarcoma Cell Growth via Regulation of YAP/p21/c-Myc Signaling

et al. 2017

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“…Previous reports have indicated that ZMYND8 (RACK7) suppresses enhancer overactivation, and ChIP-seq data showed enrichment of enhancer marks (Fig. Then, we treated MCF-7 and ZR-75-1 cells with BRD4 inhibitors (JQ1, OTX015 and CPI-0610) for 24 h, LOL expression was strongly reduced than mock in a dose-dependent manner (except for JQI treatment in ZR-75-1 cells), and the extent of downregulation was greater than that of MYC (a well-known enhancer-regulated gene) [30][31][32] (Fig. 24 In addition, the BET protein BRD4 has been reported to be essential to enhancer activity.…”

Section: Lol Is Transcribed From the Genomic Locus Of An Enhancermentioning

confidence: 97%

“…2d). Then, we treated MCF-7 and ZR-75-1 cells with BRD4 inhibitors (JQ1, OTX015 and CPI-0610) for 24 h, LOL expression was strongly reduced than mock in a dose-dependent manner (except for JQI treatment in ZR-75-1 cells), and the extent of downregulation was greater than that of MYC (a well-known enhancer-regulated gene) [30][31][32] (Fig. 2e).…”

Section: Lol Is Transcribed From the Genomic Locus Of An Enhancermentioning

confidence: 99%

“…Twenty-one pairs of tumor and para-carcinoma frozen tissues from luminal breast cancer patients and another 40 breast cancer frozen samples (20 luminal breast tumor and 20 nonluminal breast tumor) were collected immediately after the surgery from the Department of Breast Surgery at Fudan University Shanghai Cancer Center (FUSCC, Shanghai, People's Republic of China) between January 1, 2011 and December 31,2012. Histologic subgroups of these frozen tissues were determined according to their ERα expression by immunohistochemistry (IHC).…”

Section: Patients and Frozen Tissue Samplesmentioning

confidence: 99%

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Transcriptome analysis of luminal breast cancer reveals a role for LOL in tumor progression and tamoxifen resistance

Sun

Jiang

et al. 2019

Intl Journal of Cancer

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Luminal breast cancer (BC) has a sustained risk of late disease recurrence and death. Considerable numbers of patients suffer from antiendocrine therapy resistance. Here, we identified a novel lncRNA whose expression is high in breast cancer and especially higher in luminal breast cancer, dubbed LOL (lncRNA of luminal), that acts as a natural sponge for let‐7 microRNAs to regulate tumor growth and tamoxifen resistance. LOL overexpression in parental MCF‐7 cells exhibited a proliferative advantage in the addition of tamoxifen than negative control. Knocking down LOL in TamR MCF‐7 cells, recovered the sensitivity of cells to tamoxifen. Strikingly, we demonstrated that LOL is transcribed from a genomic locus of an enhancer to maintain its high expression in luminal BC and that it is extremely sensitive to enhancer‐regulating factors, such as ZMYND8 and BRD4. Estrogen deprivation or ERα signaling pathway blockage can further stimulate LOL expression, which can promote tumor progression. Clinical analysis of 374 luminal breast cancer samples indicated that LOL is an independent prognostic factor for poor survival in luminal BC. In conclusion, targeting LOL using preclinical/clinical drugs, such as BRD4 inhibitors, may represent a promising approach to inhibit luminal breast cancer progression and tamoxifen resistance.

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“…BRD binds to MYC and activates enhancer-binding protein 4 (AP4) promoters. AP4 is a key mediator of mitogenicity for proto-oncogene MYC [88]. Upon AP4 activation by MYC, repressing cell cycle arrests gene P21 [88].…”

Section: Bromodomain Inhibitorsmentioning

confidence: 99%

Epigenetic Landscape in Leukemia and Its Impact on Antileukemia Therapeutics

He¹,

Hlavka-Zhang²,

Lock³

et al. 2019

Germ Line Mutations Associated Leukemia

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Epigenomic landscape mapping in leukemia cells supports germ line mutation studies to understand pathogenicity and treatment plans. The differential regulation of gene expression and heterogeneity between cell types during hematopoiesis and leukemia development is important in understanding oncogenesis. Oncogenesis in leukemia occurs at both genomic and epigenomic levels in order for hematological cells to evade lineage commitment. To ensure that therapies target the entire malignancy, it is important to consider the regulatory network that drives malignancy caused by mutations. Therapies tailored to respond to a patient-specific epigenetic landscape have the potential to minimize risk in administering chemotherapies that may not work. In this chapter, a focused study on childhood acute lymphoblastic leukemia (ALL) will be used as an example of the current research in the field of epigenetics in leukemia and the impact it carries on our understanding of the disease and treatment plans.

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JQ1, an inhibitor of the epigenetic reader BRD4, suppresses the bidirectional MYC-AP4 axis via multiple mechanisms

Cited by 22 publications

References 29 publications

The BET Bromodomain Inhibitor JQ1 Suppresses Chondrosarcoma Cell Growth via Regulation of YAP/p21/c-Myc Signaling

The BET Bromodomain Inhibitor JQ1 Suppresses Chondrosarcoma Cell Growth via Regulation of YAP/p21/c-Myc Signaling

Transcriptome analysis of luminal breast cancer reveals a role for LOL in tumor progression and tamoxifen resistance

Epigenetic Landscape in Leukemia and Its Impact on Antileukemia Therapeutics

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