KDM5A suppresses PML-RARα target gene expression and APL differentiation through repressing H3K4me2

Epigenetic abnormalities are frequently involved in the initiation and progression of cancers, including acute myeloid leukemia (AML). A subtype of AML, acute promyelocytic leukemia (APL), is mainly driven by a specific oncogenic fusion event of promyelocytic leukemia-RA receptor fusion oncoprotein (PML-RAR alpha). PML-RAR alpha was reported as a transcription repressor through the interaction with nuclear receptor corepressor and histone deacetylase complexes leading to the mis-suppression of its target genes and differentiation blockage. Although previous studies were mainly focused on the connection of histone acetylation, it is still largely unknown whether alternative epigenetics mechanisms are involved in APL progression. KDMSA is a demethylase of histone H3 lysine 4 di- and tri-methylations (H3K4me2/3) and a transcription corepressor. Here, we found that the loss of KDM5A led to APL NB4 cell differentiation and retarded growth. Mechanistically, through epigenomics and transcriptomics analyses, KDM5A binding was detected in 1889 genes, with the majority of the binding events at promoter regions. KDM5A suppressed the expression of 621 genes, including 42 PML-RARa target genes, primarily by controlling the H3K4me2 in the promoters and 5' end intragenic regions. In addition, a recently reported pan-KDM5 inhibitor, CPI-455, on its own could phenocopy the differentiation effects as KDMSA loss in NB4 cells. CPI-455 treatment or KDMSA knockout could greatly sensitize NB4 cells to all-trans retinoic acid-induced differentiation. Our findings indicate that KDM5A contributed to the differentiation blockage in the APL cell line NM, and inhibition of KDMSA could greatly potentiate NB4 differentiation.

Automated summary

Epigenetic abnormalities play a critical role in cancer, specifically in diseases like AML where aberrant fusion proteins drive the disease. The loss of KDM5A leads to differentiation and growth retardation in APL NB4 cells, by suppressing the expression of key target genes. Inhibition of KDMSA could greatly enhance differentiation in NB4 cells, suggesting a potential therapeutic target in APL treatment.