BET inhibitor suppresses migration of human hepatocellular carcinoma by inhibiting SMARCA4

Hae In Choi,Mina Baek,Eunyoung Yoo,Young Gyu Chai,Young Seek Lee,Jin Choul Chai,Ga Yeong An,Kyoung Hwa Jung

doi:10.1038/s41598-021-91284-2

Abstract

Hepatocellular carcinoma (HCC) is one of the most prevalent and poorly responsive cancers worldwide. Bromodomain and extraterminal (BET) inhibitors, such as JQ1 and OTX-015, inhibit BET protein binding to acetylated residues in histones. However, the physiological mechanisms and regulatory processes of BET inhibition in HCC remain unclear. To explore BET inhibitors’ potential role in the molecular mechanisms underlying their anticancer effects in HCC, we analyzed BET inhibitor-treated HCC cells’ gene expression profiles with RNA-seq and bioinformatics analysis. BET inhibitor treatment significantly downregulated genes related to bromodomain-containing proteins 4 (BRD4), such as ACSL5, SLC38A5, and ICAM2. Importantly, some cell migration-related genes, including AOC3, CCR6, SSTR5, and SCL7A11, were significantly downregulated. Additionally, bioinformatics analysis using Ingenuity Knowledge Base Ingenuity Pathway Analysis (IPA) revealed that SMARCA4 regulated migration response molecules. Furthermore, knockdown of SMARCA4 gene expression by siRNA treatment significantly reduced cell migration and the expression of migration-related genes. In summary, our results indicated that BET inhibitor treatment in HCC cell lines reduces cell migration through the downregulation of SMARCA4.

Highlights

Hepatocellular carcinoma (HCC) is one of the most prevalent and poorly responsive cancers worldwide
We found that Bromodomain and extraterminal (BET) inhibition decreased the proportion of EdUpositive cells for 24 h and 48 h, indicating that BET inhibition reduced the proliferation of HCC cell lines
These results suggest that HCC cell line proliferation was inhibited in BET inhibitor-treated cells, as expected (Fig. 1b)

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most prevalent and poorly responsive cancers worldwide. BET inhibitor treatment significantly downregulated genes related to bromodomain-containing proteins 4 (BRD4), such as ACSL5, SLC38A5, and ICAM2. Abbreviations HCC Hepatocellular carcinoma BRD4 Bromodomain-containing proteins 4 SMARCA4 SWI/SNF related, matrix associated, actin-dependent regulator of chromatin, subfamily a, member 4 DEG Differentially expressed genes qPCR Quantitative reverse transcription-polymerase chain reaction RNA-seq RNA-sequencing. HCC initiation and progression are driven by the accumulation of several aberrations and dysregulation of the genome and e pigenome[3,4,5,6] These anomalies induce gene expression changes and give way to highly regulated gene expression, including gene networks and epigenetic modifications in essential for cell death, cell migration, and tumor g rowth[7,8,9,10,11]. Since the BET inhibitor JQ1 reported[24], many other clinically efficacious BET inhibitors have been identified and published, including GSK525762, birabresib (OTX-015), and ABBV-07525

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Discussion

Conclusion