Histone acetylation by HBO1 (KAT7) activates Wnt/β-catenin signaling to promote leukemogenesis in B-cell acute lymphoblastic leukemia

Abstract

B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive hematological disorder with a dismal prognosis. The dysregulation of histone acetylation is of great significance in the pathogenesis and progression of B-ALL. Regarded as a fundamental acetyltransferase gene, the role of HBO1 (lysine acetyltransferase 7/KAT7) in B-ALL has not been investigated. Herein, we found that HBO1 expression was elevated in human B-ALL cells and associated with poor disease-free survival. Strikingly, HBO1 knockdown inhibited viability, proliferation, and G1-S cycle progression in B-ALL cells, while provoking apoptosis. In contrast, ectopic overexpression of HBO1 enhanced cell viability and proliferation but inhibited apoptotic activation. The results of in vivo experiments also certificated the inhibitory effect of HBO1 knockdown on tumor growth. Mechanistically, HBO1 acetylated histone H3K14, H4K8, and H4K12, followed by upregulating CTNNB1 expression, resulting in activation of the Wnt/β-catenin signaling pathway. Moreover, a novel small molecule inhibitor of HBO1, WM-3835, potently inhibited the progression of B-ALL. Our data identified HBO1 as an efficacious regulator of CTNNB1 with therapeutic potential in B-ALL.

Recurrent UBE3C-LRP5 translocations in head and neck cancer with therapeutic implications

“…Consistent with these reports, ectopic expression of the UBE3C-LRP5 (v7) splice variant was the most activating, with a higher number of soft agar colonies, compared to other LRP5-UBE3C (v1) and UBE3C-LRP5 (v1, v2) fusion variants, possibly because of the absence of the DKK1 inhibitory domain of LRP5 in the UBE3C-LRP5 (v7) fusion. Immunofluorescence and western blot analysis of nuclear and cytoplasmic cell fractionation revealed a significantly high accumulation of β-catenin in the nuclear fraction of cells upon overexpression of UBE3C-LRP5 fusion, indicating constitutive activation of the Wnt/β-catenin pathway with upregulated target genes, MYC , CCND1 37 – 39 , LEF1 , and TCF4 40 – 44 as reported in the literature for multiple cancers. We found that overexpression of UBE3C-LRP5 fusion significantly increased the clonogenic, migratory, and invasive potential of head and neck cancer cells by activating the Wnt/β-catenin pathway, whereas transient knockdown of the fusion, but not full-length LRP5 , suppresses these phenotypes.…”