Abstract
Epigenetic deregulation plays an essential role in hepatocellular carcinoma (HCC) progression. Bromodomains are epigenetic “readers” of histone acetylation. Recently, bromodomain inhibitors have exhibited promising therapeutic potential for cancer treatment. Using transcriptome sequencing, we identified BRPF1 (bromodomain and PHD finger containing 1) as the most significantly upregulated gene among the 43 bromodomain-containing genes in human HCC. BRPF1 upregulation was significantly associated with poor patient survival. Gene ablation or pharmacological inactivation of BRPF1 significantly attenuated HCC cell growth in vitro and in vivo. BRPF1 was involved in cell cycle progression, senescence and cancer stemness. Transcriptome sequencing revealed that BRPF1 is a master regulator controlling the expression of multiple key oncogenes, including E2F2 and EZH2. We demonstrated that BRPF1 activated E2F2 and EZH2 expression by facilitating promoter H3K14 acetylation through MOZ/MORF complex. In conclusion, BRPF1 is frequently upregulated in human HCCs. Targeting BRPF1 may be an approach for HCC treatment.
Highlights
Epigenetic deregulation plays an essential role in hepatocellular carcinoma (HCC) progression
The results showed that upregulation of bromodomain-containing genes is a common phenomenon in human HCC, implying that the demand for reading acetylation marks is increased for HCC cell growth
Since our initial data suggested that BRPF1 may be a potential therapeutic target to suppress HCC growth, we investigated the therapeutic potential of GSK5959, a BRPF1-specific inhibitor, in HCC. (Fig. 5a)
Summary
Epigenetic deregulation plays an essential role in hepatocellular carcinoma (HCC) progression. We identified BRPF1 (bromodomain and PHD finger containing 1) as the most significantly upregulated gene among the 43 bromodomain-containing genes in human HCC. BRPF1 upregulation was significantly associated with poor patient survival. Transcriptome sequencing revealed that BRPF1 is a master regulator controlling the expression of multiple key oncogenes, including E2F2 and EZH2. BRPF1 is frequently upregulated in human HCCs. Targeting BRPF1 may be an approach for HCC treatment. 1234567890():,; Hepatocellular carcinoma (HCC) is the most common type of liver cancer, accounting for ~80% of primary liver cancers[1]. Symptoms usually appear at the late stage of HCC, and metastasis is commonly observed in HCC patients[5]. Liver transplantation or surgical resection is not applicable for patients diagnosed at the late stage of HCC6. Targeted therapy is the major method for the treatment of advanced HCC
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