Inhibition of BRD4 suppresses tumor growth and enhances iodine uptake in thyroid cancer

Gao, Xuemei; Wu, Xinchao; Zhang, X; Hua, Wenjuan; Zhang, Yajing; Maimaiti, Yusufu; Gao, Zairong; Zhang, Yongxue

doi:10.1016/j.bbrc.2015.12.008

Cited by 52 publications

(44 citation statements)

References 29 publications

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“…It has been reported that JQ1 treatment inhibited proliferation of Ewing sarcoma cells in vitro and reduced tumor growth in vivo in a dose dependent manner [25]. Inhibition of BRD4 in thyroid cancer cells by JQ1 has been demonstrated to decrease cell viability in vitro and suppress tumor growth in vivo [8]. Similar inhibitory effect of JQ1 was observed in many other malignant tumors including melanoma, HCC and ovarian cancer [9, 10, 26].…”

Section: Introductionmentioning

confidence: 82%

BRD4 inhibition suppresses cell growth, migration and invasion of salivary adenoid cystic carcinoma

Wang

et al. 2017

Biol Res

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BackgroundBromodomain-containing protein 4 (BRD4) inhibition is a new therapeutic strategy for many malignancies. In this study, we aimed to explore the effect of BRD4 inhibition by JQ1 on in vitro cell growth, migration and invasion of salivary adenoid cystic carcinoma (SACC).MethodsThe human normal epithelial cells and SACC cells (ACC-LM and ACC-83) were treated with JQ1 at concentrations of 0, 0.1, 0.5 or 1 μM. Cell Counting Kit-8 (CCK-8) assay was performed to evaluate cell proliferation. Cell apoptosis and cell cycle distribution was evaluated by Flow cytometry. Immunofluorescence staining was used to examine the expression of BRD4 in SACC cells. The quantitative real-time polymerase chain reaction (qRT-PCR) assay and western blot assay were performed to examine messenger RNA (mRNA) and protein levels in SACC cells. Wound-healing assay and transwell assay were used to evaluate the activities of migration and invasion of SACC cells.ResultsJQ1 exhibits no adverse effects on proliferation, cell cycle and cell apoptosis of the normal human epithelial cells, while suppressed proliferation and cell cycle, and induced apoptosis of SACC cells, down-regulated the mRNA and protein levels of BRD4 in SACC cells, meanwhile reduced protein expressions of c-myc and BCL-2, two known target genes of BRD4. Moreover, JQ1 inhibited SACC cell migration and invasion by regulating key epithelial–mesenchymal transition (EMT) characteristics including E-cadherin, Vimentin and Twist.ConclusionsBRD4 is an important transcription factor in SACC and BRD4 inhibition by JQ1 may be a new strategy for SACC treatment.

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Section: Introductionmentioning

confidence: 82%

BRD4 inhibition suppresses cell growth, migration and invasion of salivary adenoid cystic carcinoma

Wang

et al. 2017

Biol Res

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“…Previous study has showed that BRD4 is involved in the progression of PTC (20). BRD4 silencing decreased the tumor viability, proliferation in vitro and in vivo (20).…”

Section: Uca1 Is Upregulated In Ptc Tissues and Cell Linesmentioning

confidence: 91%

Long non‑coding RNA UCA1 promotes papillary thyroid cancer cell proliferation via miR‑204‑mediated BRD4 activation

et al. 2018

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Long non‑coding RNA (lncRNA) urothelial carcinoma‑associated 1 (UCA1) has been used in tumor development and progression in many types of cancer. However, the function and mechanism underlying the action of UCA1 in papillary thyroid cancer (PTC) remains unclear. Therefore, these topics were investigated in the present study by in vitro and in vivo experiments. It was demonstrated that the expression level of UCA1 was more significantly upregulated in PTC cell lines and tissues when compared with the immortal human thyroid follicular cell line and adjacent normal tissues, respectively. UCA1 knockdown significantly inhibited PTC cell viability, colony formation and the bromodomain containing 4 (BRD4) expression level in vitro, and retarded PTC tumor growth in vivo. In the previous study, microRNA (miR)‑204 inhibited thyroid cancer progression and was regulated by UCA1 in other types of cancer. In addition, by conducting dual luciferase reporter assays, it was confirmed that miR‑204 directly binds to UCA1 and the 3'‑untranslated region of BRD4. Furthermore, UCA1 competed with BRD4 for miR‑204 binding. miR‑204 knockdown enhanced BRD4 expression, which can be partially restored by short hairpin‑UCA1. The results of the present study illustrated that UCA1 promotes PTC progression by acting as a competing endogenous RNA by sponging miR‑204. In conclusion, UCA1 may be regarded as an oncogenic lncRNA, promoting PTC cell proliferation, and be a potential target for human PTC treatment.

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“…Inhibitors of BET proteins have shown potent inhibitory activity against hematological malignant cancers and other types such as glioblastoma and lung and prostate cancers (8-11). Although it has been shown that JQ1 inhibits growth of established differentiated thyroid cancer cells in nude mice (12), the therapeutic efficacy of BET inhibitors in undifferentiated thyroid cancers has yet to be studied.…”

Section: Introductionmentioning

confidence: 99%

Bromodomain and Extraterminal Protein Inhibitor JQ1 Suppresses Thyroid Tumor Growth in a Mouse Model

Zhu

Enomoto

Zhao

et al. 2017

Clinical Cancer Research

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Purpose New therapeutic approaches are needed for patients with thyroid cancer refractory to radioiodine treatment. An inhibitor of bromodomain and extraterminal domain (BET) proteins, JQ1, shows potent anti-tumor effects in hematological cancers and solid tumors. To evaluate whether JQ1 is effective against thyroid cancer, we examined anti-tumor efficacy of JQ1 using the ThrbPV/PVKrasG12D mouse, a model of anaplastic thyroid cancer. Experimental Design We treated ThrbPV/PVKrasG12D mice with vehicle or JQ1 at a dose of 50 mg/kg body weight/day starting at the age of 8 weeks for a 10-week period and monitored thyroid tumor progression. Results JQ1 markedly inhibited thyroid tumor growth and prolonged survival of these mice. Global differential gene expression analysis showed that JQ1 suppressed the cMyc (hereafter referred to as Myc) transcription program by inhibiting mRNA expression of Myc, ccnd1, and other related genes. JQ1-suppressed Myc expression was accompanied by chromatin remodeling as evidenced by increased expression of histones and hexamethylene bis-acetamide inducible 1, a suppressor of RNA polymerase II transcription elongation. Analyses showed that JQ1 decreased MYC abundance in thyroid tumors and attenuated the cyclin-CDK4-Rb-E2F3 signaling to decrease tumor growth. Further analysis indicated that JQ1 inhibited the recruitment of BDR4 to the promoter complex of the Myc and Ccnd1 genes in rat thyroid follicular PCCL3 cells, resulting in decreased MYC expression at the mRNA and protein levels to inhibit tumor cell proliferation. Conclusions These preclinical findings suggest that BET inhibitors may be an effective agent to reduce thyroid tumor burden for the treatment of refractory thyroid cancer.

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Inhibition of BRD4 suppresses tumor growth and enhances iodine uptake in thyroid cancer

Cited by 52 publications

References 29 publications

BRD4 inhibition suppresses cell growth, migration and invasion of salivary adenoid cystic carcinoma

BRD4 inhibition suppresses cell growth, migration and invasion of salivary adenoid cystic carcinoma

Long non‑coding RNA UCA1 promotes papillary thyroid cancer cell proliferation via miR‑204‑mediated BRD4 activation

Bromodomain and Extraterminal Protein Inhibitor JQ1 Suppresses Thyroid Tumor Growth in a Mouse Model

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