AUTHOR=Situ Yongli , Liang Quanyan , Zeng Ziying , Chen Jv , Shao Zheng , Xu Qinying , Lu Xiaoyong , Cui Yongshi , Zhang Juying , Lu Lingling , Deng Li 

TITLE=Systematic analysis of the BET family in adrenocortical carcinoma: The expression, prognosis, gene regulation network, and regulation targets

JOURNAL=Frontiers in Endocrinology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2023.1089531

DOI=10.3389/fendo.2023.1089531

ISSN=1664-2392

ABSTRACT=<sec><title>Background</title><p>Bromodomain and extracellular terminal (BET) family (including BRD2, BRD3, and BRD4) is considered to be a major driver of cancer cell growth and a new target for cancer therapy. Currently, more than 30 targeted inhibitors have shown significant inhibitory effects against various tumors in preclinical and clinical trials. However, the expression levels, gene regulatory networks, prognostic value, and target prediction of <italic>BRD2</italic>, <italic>BRD3</italic>, and <italic>BRD4</italic> in adrenocortical carcinoma (ACC) have not been fully elucidated. Therefore, this study aimed to systematically analyze the expression, gene regulatory network, prognostic value, and target prediction of <italic>BRD2</italic>, <italic>BRD3</italic>, and <italic>BRD4</italic> in patients with ACC, and elucidated the association between BET family expression and ACC. We also provided useful information on <italic>BRD2</italic>, <italic>BRD3</italic>, and <italic>BRD4</italic> and potential new targets for the clinical treatment of ACC.</p></sec><sec><title>Methods</title><p>We systematically analyzed the expression, prognosis, gene regulatory network, and regulatory targets of <italic>BRD2</italic>, <italic>BRD3</italic>, and <italic>BRD4</italic> in ACC using multiple online databases, including cBioPortal, TRRUST, GeneMANIA, GEPIA, Metascape, UALCAN, LinkedOmics, and TIMER.</p></sec><sec><title>Results</title><p>The expression levels of <italic>BRD3</italic> and <italic>BRD4</italic> were significantly upregulated in ACC patients at different cancer stages. Moreover, the expression of <italic>BRD4</italic> was significantly correlated with the pathological stage of ACC. ACC patients with low <italic>BRD2</italic>, <italic>BRD3</italic>, and <italic>BRD4</italic> expressions had longer survival than patients with high <italic>BRD2</italic>, <italic>BRD3</italic>, and <italic>BRD4</italic> expressions. The expression of <italic>BRD2</italic>, <italic>BRD3</italic>, and <italic>BRD4</italic> was altered by 5%, 5%, and 12% in 75 ACC patients, respectively. The frequency of gene alterations in the 50 most frequently altered <italic>BRD2</italic>, <italic>BRD3</italic>, and <italic>BRD4</italic> neighboring genes in these ACC patients were ≥25.00%, ≥25.00%, and ≥44.44%, respectively. <italic>BRD2</italic>, <italic>BRD3</italic>, and <italic>BRD4</italic> and their neighboring genes form a complex network of interactions mainly through co-expression, physical interactions, and shared protein domains. Molecular functions related to <italic>BRD2</italic>, <italic>BRD3</italic>, and <italic>BRD4</italic> and their neighboring genes mainly include protein-macromolecule adaptor activity, cell adhesion molecule binding, and aromatase activity. Chemokine signaling pathway, thiamine metabolism, and olfactory transduction were found to be enriched as per the KEGG pathway analysis. SP1, NPM1, STAT3, and TP53 are key transcription factors for <italic>BRD2</italic>, <italic>BRD4</italic>, and their neighboring genes. MiR-142-3P, miR-484, and miR-519C were the main miRNA targets of <italic>BRD2</italic>, <italic>BRD3</italic>, BRD4, and their neighboring genes. We analyzed the mRNA sequencing data from 79 patients with ACC and found that <italic>ZSCAN12</italic>, <italic>DHX16</italic>, <italic>PRPF4B</italic>, <italic>EHMT1</italic>, <italic>CDK5RAP2</italic>, <italic>POMT1</italic>, <italic>WIZ</italic>, <italic>ZNF543</italic>, and <italic>AKAP8</italic> were the top nine genes whose expression were positively associated with <italic>BRD2</italic>, <italic>BRD3</italic>, and <italic>BRD4</italic> expression. The expression level of <italic>BRD2</italic>, <italic>BRD3</italic>, and <italic>BRD4</italic> positively correlated with B cell and dendritic cell infiltration levels. <italic>BRD4</italic>-targeted drug PFI-1 and (<italic>BRD2</italic>, <italic>BRD3</italic>, and <italic>BRD4</italic>)-targeted drug I-BET-151 may have good inhibitory effects on the SW13 cell line.</p></sec><sec><title>Conclusions</title><p>The findings of this study provide a partial basis for the role of <italic>BRD2</italic>, <italic>BRD3</italic>, and <italic>BRD4</italic> in the occurrence and development of ACC. In addition, this study also provides new potential therapeutic targets for ACC, which can serve as a reference for future basic and clinical research.</p></sec>