Bromodomain protein BRD4 is an epigenetic activator of B7-H6 expression in acute myeloid leukemia.

Abstract

B7-H6, a ligand for the NK activating receptor NKp30, has been identified as a biomarker of poor prognosis in several solid cancers. However, little is known about the role of B7-H6 and the mechanisms that control its expression in acute myeloid leukemia (AML). Epigenome modulation, including epigenomic reader dysregulation, is one of the hallmarks of AML. Bromodomain-containing protein 4 (BRD4), the best-known member of the BET family of epigenetic readers, is overexpressed in AML cells and regulates the transcription of genes involved in the pathogenesis of AML, as MYC oncogene. Here, we analyze the role of BRD4 in regulating B7-H6 in AML cells. Results demonstrated that the specific inhibition of BRD4 drastically reduces the expression of B7-H6 in AML cells. Histone acetylation mediated by CBP30/P300 facilitates the binding of BRD4 to the B7-H6 promoter, which recruits the P-TEFb elongation factor that phosphorylates RNA polymerase II, thereby activating B7-H6 transcription. BRD4 also co-bounded with JMJD6 at the distal enhancer of the B7-H6 gene. Metabolic modulation with metformin modifies the acetylation pattern in the B7-H6 promoter, impairing BRD4 binding, thereby inhibiting B7-H6 expression. B7-H6 knockdown induces the apoptosis in HEL-R cell line. Moreover, a high level of B7-H6 expression in AML patients is related to increased BRD4 levels, myelodysplastic-derived AML, and del5q, the two latter being associated with poor prognosis. Our data show that BRD4 is a positive regulator of the pro-tumorigenic molecule B7-H6 and that the blockage of the B7-H6 is a potential therapeutic target for the treatment of AML.

• Authors: Aroa Baragaño Raneros, Ramon M Rodriguez, Aida Bernardo Flórez, Pilar Palomo, Enrique Colado, Alfredo Minguela, Beatriz Suárez Álvarez, Carlos López-Larrea
• Journal: Oncoimmunology (Oncoimmunology) Vol. 10 Issue 1 Pg. 1897294 (03 25 2021) ISSN: 2162-402X [Electronic] United States
• PMID: 33796404 (Publication Type: Journal Article)
• Copyright: © 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.

Chemical References

• B7 Antigens
• BRD4 protein, human
• Cell Cycle Proteins
• NCR3LG1 protein, human
• Natural Cytotoxicity Triggering Receptor 3
• Transcription Factors
• JMJD6 protein, human
• Jumonji Domain-Containing Histone Demethylases

Topics

• B7 Antigens
• Cell Cycle Proteins (genetics)
• Cell Line, Tumor
• Epigenesis, Genetic (genetics)
• Humans
• Jumonji Domain-Containing Histone Demethylases
• Leukemia, Myeloid, Acute (genetics)
• Natural Cytotoxicity Triggering Receptor 3 (genetics)
• Transcription Factors (genetics)