Analysis of the anti-tumor mechanism of BRD4 inhibition in hepatocellular carcinoma

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K17468
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Sapporo Medical University
• Principal Investigator: Sasaki Hajime 札幌医科大学, 医学部, 訪問研究員 (30784441)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: 肝細胞がん / ヒストン修飾 / エピジェネティクス / がん治療 / BET阻害剤 / BRD4阻害剤

Outline of Final Research Achievements

BRD4 inhibitors exert anti-tumor effects in various cancers, including hepatocellular carcinoma (HCC). We investigated the mechanism underlying the anti-tumor effects of BRD4 inhibition in HCC. We first tested the effects of the BRD4 inhibitor JQ1 in a series of 9 HCC cell lines and found that it strongly suppressed HCC cell proliferation by inducing cell cycle arrest and apoptosis. Gene expression microarray analysis revealed that JQ1 also induced marked changes in the gene expression profiles of HCC cells, and genes associated with cell cycle and apoptosis were significantly enriched among the affected genes. Notably, a number of cancer-related genes, including BCAT1, DDR1, GDF15, FANCD2, SENP1 and TYRO3, were strongly suppressed by JQ1 in HCC cells. We also confirmed BRD4 bound within the promoter regions of these genes, which suggests they are targets of BRD4 in HCC cells. JQ1 thus appears to exert its anti-tumor effects in HCC by suppressing multiple BRD4 target genes.

Free Research Field

消化器内科学

Academic Significance and Societal Importance of the Research Achievements

肝細胞がんは多発や再発が多い腫瘍であり、進行肝細胞がんに対する治療法の開発は社会的意義が大きい。BRD4阻害剤の抗腫瘍効果は様々な癌種において報告されているが、肝細胞癌における研究論文はいまだ少なく、抗腫瘍メカニズムの全容は解明されていない。我々は、複数の肝がん細胞株のトランスクリプトーム解析から、複数の新規BRD4標的遺伝子候補を同定した。これらの遺伝子はいずれも肝がんで発現上昇しており、かつ発がんとの関わりがこれまでに報告されていることから、抗腫瘍効果に関わることが推測された。本研究から、BRD4阻害による肝がんの抗腫瘍効果メカニズムの一端が解明された。