N-terminal histone acetyltransferase NAA40 modulates osteosarcoma progression by controlling AGR2 expression

Osteosarcoma (OS) is the most common primary malignant bone neoplasm in children and adolescents, characterized by high mortality and disability owing to frequent relapse and metastasis. However, N-alpha-acetyltransferase 40 (NAA40) molecular mechanisms underlying OS progression and metastasis remain unexplored.

Bioinformatics analysis was used to evaluate NAA40 role in OS data from GEO and TARGET database. OS cell multiplication, invasion and migration were gauged in CCK8, EdU assays, and Transwell assays. RT-qPCR, ChIP-qPCR, dual luciferase reporter assay and rescue experiments were to explore NAA40 regulatory mechanism. Animal experiments further confirmed cell-based assays and NAA40 molecular mechanism.

Herein NAA40 expression was upregulated in OS samples and associated with shorter survival among patients. Functionally, NAA40 depletion resulted in reduced OS cell viability, decreased migration, and invasion in vitro. Mechanistically, NAA40 loss was associated with increased H4S1ph and H4R3me2a and decreased H4R3me2s.NAA40 overexpression improved the transcriptional activity in the promoter of AGR2. Histone marks, H3K4me3 and H3K27me3, at the AGR2 promoter were altered, inducing changes in AGR2 expression in NAA40-depleted OS cells. Anterior gradient 2 (AGR2) was identified as a downstream target of NAA40.AGR2 knockdown in OS cells resulted in reduced viability, decreased migration, and invasion. Ectopic overexpression of AGR2 partially rescued these phenotypic changes. In vivo experiments revealed that NAA40 depletion led to reduced AGR2 protein levels, inhibiting the proliferative and metastatic potential of OS cells.

NAA40 contributes to OS development and progression by epigenetically regulating AGR2 expression.