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BRD4 as a therapeutic target for nonfunctioning and growth hormone pituitary adenoma.

ABSTRACT: BACKGROUND:Nonfunctioning pituitary adenoma (NFPA) and growth hormone pituitary adenoma (GHPA) are major subtypes of pituitary adenomas (PAs). The primary treatment is surgical resection. However, radical excision remains challenging, and few effective medical therapies are available. It is urgent to find novel targets for the treatment. Bromodomain-containing protein 4 (BRD4) is an epigenetic regulator that leads to aberrant transcriptional activation of oncogenes. Herein, we investigated the pathological role of BRD4 and evaluated the effectiveness of BRD4 inhibitors in the treatment of NFPA and GHPA. METHODS:The expression of BRD4 was detected in NFPA, GHPA, and normal pituitary tissues. The efficacies of BRD4 inhibitors were evaluated in GH3 and MMQ cell lines, patient-derived tumor cells, and in vivo mouse xenograft models of PA. Standard western blots, real-time PCR, and flow cytometry experiments were performed to investigate the effect of BRD4 inhibitors on cell cycle progression, apoptosis, and the expression patterns of downstream genes. RESULTS:Immunohistochemistry studies demonstrated the overexpression of BRD4 in NFPA and GHPA. In vitro and in vivo studies showed that treatment with the BRD4 inhibitor ZBC-260 significantly inhibited the proliferation of PA cells. Further mechanistic studies revealed that ZBC-260 could downregulate the expression of c-Myc, B-cell lymphoma 2 (Bcl2), and related genes, which are vital factors in pituitary tumorigenesis. CONCLUSION:In this study, we determined the overexpression of BRD4 in NFPA and GHPA and assessed the effects of BRD4 inhibitors on PA cells in vitro and in vivo. Our findings suggest that BRD4 is a promising therapeutic target for NFPA and GHPA.

SUBMITTER: Shi C

PROVIDER: S-EPMC7594556 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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BRD4 as a therapeutic target for nonfunctioning and growth hormone pituitary adenoma.

Shi Chengzhang C Ye Zhao Z Han Jie J Ye Xiaoqing X Lu Wenchao W Ji Chenxing C Li Zizhou Z Ma Zengyi Z Zhang Qilin Q Zhang Yichao Y He Wenqiang W Chen Zhengyuan Z Cao Xiaoyun X Shou Xuefei X Zhou Xiang X Wang Yongfei Y Zhang Zhaoyun Z Li Yiming Y Ye Hongying H He Min M Chen Hong H Cheng Haixia H Sun Jun J Cai Jianyong J Huang Chuanxin C Ye Fei F Luo Cheng C Zhou Bing B Ding Hong H Zhao Yao Y

Neuro-oncology 20200801 8

<h4>Background</h4>Nonfunctioning pituitary adenoma (NFPA) and growth hormone pituitary adenoma (GHPA) are major subtypes of pituitary adenomas (PAs). The primary treatment is surgical resection. However, radical excision remains challenging, and few effective medical therapies are available. It is urgent to find novel targets for the treatment. Bromodomain-containing protein 4 (BRD4) is an epigenetic regulator that leads to aberrant transcriptional activation of oncogenes. Herein, we investigat ...[more]

PMID: 32246150

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Project description:PurposeThis study aimed to investigate the value of magnetic resonance (MR) characteristics in differentiating the subtypes of growth hormone pituitary adenomas.Materials and methodsThe clinical and MR imaging data of 70 patients with growth hormone pituitary adenoma confirmed by surgery and pathology were retrospectively analyzed. The tumors were divided into dense granular (DG; 36 cases) and sparse granular subtypes (SG; 34 cases). The tumors' MR features were analyzed, including the mean and maximum diameters, T2 signal intensity, T2 relative signal intensity (rSI), homogeneity, enhancement degree, and invasiveness (Knosp grade). Mann-Whitney U test and χ2 test were used to analyze MR characteristics between the 2 groups. The independent predictors and predictive probabilities of tumor subtypes were obtained via a logistic regression model, and the efficacy was compared by receiver operating characteristic curve.ResultsThe mean and maximum diameters of growth hormone adenoma in DG and SG were 1.77 versus 2.45 and 1.95 versus 3.00 cm (median, P < 0.05), respectively. There was a significant difference between the 2 groups in T2 signal intensity and rSI (P values were 0.02 and 0.001, respectively). Most DG adenomas (86.1%) appeared as hypointense on T2 images, and 38.2% of SG adenomas were hyperintense. There was no significant difference in tumor homogeneity (P = 0.622). A significant difference was found in the Knosp grade between the 2 subtypes (P = 0.004). In addition, the enhancement degree of SG adenomas was significantly higher than that of DG adenomas (P = 0.001). Logistic regression analysis showed that high T2 rSI value and marked contrast enhancement were independent predictors of the 2 subtypes, and the odds ratios were 4.811 and 4.649, respectively. The multivariate logistic model obtained relatively high predicting efficacy, and the area under the curve, sensitivity, and specificity were 0.765, 0.882, and 0.500, respectively.ConclusionsThere are significant differences in tumor size, T2 signal intensity, T2 rSI, enhancement degree, and invasiveness between DG and SG adenomas. The logistic model based on the marked contrast enhancement and high T2 rSI value has an important value in predicting the subtype of growth hormone adenoma.

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BRD4 as a therapeutic target for nonfunctioning and growth hormone pituitary adenoma.

Publications

BRD4 as a therapeutic target for nonfunctioning and growth hormone pituitary adenoma.

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