Abstract
Bromodomain-containing protein 9 (BRD9) has a critical role in human squamous cell lung cancer, acute myeloid leukemia, and malignant rhabdoid tumors. However, the expression and biological role of BRD9 in hepatocellular carcinoma (HCC) is poorly understood. In this study, BRD9 expression was found to be elevated in HCC through data mining of public databases. Next, we confirmed that the expression of BRD9 was increased in HCC tissues compared with that in adjacent non-tumor tissues. The upregulated level of BRD9 was also observed in HCC cells in comparison to LO2 cells. The increased BRD9 expression was correlated with unfavorable clinicopathological features. A high level of BRD9 predicted a poorer overall survival and disease-free survival of HCC patients. Functionally, BRD9 overexpression facilitated the proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) of Hep3B cells. Conversely, either BRD9 depletion or pharmacological inhibition of BRD9 resulted in the reduced proliferation and invasiveness of HCCLM3 cells. In addition, the BRD9 knockdown restrained the growth and metastasis of HCCLM3 cells in vivo. Mechanistically, BRD9 positively regulated TUFT1 expression and AKT activation in HCC cells. ChIP-qPCR analysis indicated that BRD9 promoted the binding of P300 acetyltransferase to the TUFT1 promoter and epigenetically regulated TUFT1 expression by increasing H3K27Ac in the promoter. Notably, either TUFT1 knockdown or AKT inhibitor (MK2206) abrogated the promoting effects of BRD9 on the proliferation, migration, invasion, and EMT of Hep3B cells. The forced expression of TUFT1 abolished the effects of BRD9 knockdown on the growth and metastasis of HCCLM3 cells. Altogether, these data indicate that BRD9 promotes the growth and metastasis of HCC cells by activating the TUFT1/AKT pathway and may serve as a promising biomarker and therapeutic target for HCC.
Highlights
Hepatocellular carcinoma (HCC) is ranked as the sixth most common malignancy and the third leading cause of cancer-related mortality, with ~780,000 newly diagnosedOfficial journal of the Cell Death Differentiation AssociationDou et al Cell Death and Disease (2020)11:730 can facilitate the development of novel targeted drugs and result in the improvement of overall prognosis.Recently, bromodomain-containing protein 9 (BRD9) was identified to be a component of the SWI-SNF chromatin-remodeling complex, which participates in gene transcription, DNA repair, and cell differentiation[5]
In this study, we identify BRD9 as a key oncogenic regulator of HCC growth and metastasis and reveal the mechanism underlying the biological functions of BRD9 in HCC
We demonstrated that the level of BRD9 was upregulated in HCC tissues by analyzing data from publicly available databases and measuring the expression level of BRD9 using Quantitative real-time PCR (qRT-PCR), western blotting, and IHC in the resected HCC tissues
Summary
Bromodomain-containing protein 9 (BRD9) was identified to be a component of the SWI-SNF chromatin-remodeling complex, which participates in gene transcription, DNA repair, and cell differentiation[5]. In AML cells, BRD9 binds to BRG1 and is essential for supporting enhancermediated MYC expression[8,9]. Inhibitors of BRD9 suppressed the proliferation of mouse and human AML cells[8]. BRD9 was found to promote AML cell survival primarily by regulating the SOCS3-STAT5 pathway[10]. In basal cell carcinoma (BCC), BRD9 was upregulated in both murine and human HHi (Hedgehog inhibitors)-resistant BCC. An inhibitor of BRD9 reversed HHi resistance and restored the vismodegib sensitivity of BCC12. BRD9 inhibition in rhabdoid tumors resulted in decreased cell proliferation, G1-arrest, and apoptosis[13].
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