Background:Multiple myeloma(MM)is the second most common hematological malignancy.An overwhelming majority of patients with MM progress to serious osteolytic bone disease.Aminoacyl-tRNA synthetase-interacting multifun...Background:Multiple myeloma(MM)is the second most common hematological malignancy.An overwhelming majority of patients with MM progress to serious osteolytic bone disease.Aminoacyl-tRNA synthetase-interacting multifunctional protein 1(AIMP1)participates in several steps during cancer development and osteoclast differentiation.This study aimed to explore its role in MM.Methods:The gene expression profiling cohorts of MM were applied to determine the expression of AIMP1 and its association with MM patient prognosis.Enzyme-linked immunosorbent assay,immunohistochemistry,and Western blotting were used to detect AIMP1 expression.Protein chip analysis,RNA-sequencing,and chromatin immunoprecipitation and next-generation sequencing were employed to screen the interacting proteins and key downstream targets of AIMP1.The impact of AIMP1 on cellular proliferation was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)assay in vitro and a xenograft model in vivo.Bone lesions were evaluated using tartrate-resistant acid phosphatase staining in vitro.A NOD/SCID-TIBIA mouse model was used to evaluate the effect of siAIMP1-loaded exosomes on bone lesion formation in vivo.Results:AIMP1 expression was increased in MM patients and strongly associated with unfavorable outcomes.Increased AIMP1 expression promoted MM cell proliferation in vitro and in vivo via activation of the mitogen-activated protein kinase(MAPK)signaling pathway.Protein chip assays and subsequent experiments revealed that AIMP1 interacted with acidic leucine-rich nuclear phosphoprotein 32 family member A(ANP32A)to regulate histone H3 acetylation.In addition,AIMP1 increased histone H3 acetylation enrichment function of GRB2-associated and regulator of MAPK protein 2(GAREM2)to increase the phosphorylation of extracellular-regulated kinase 1/2(p-ERK1/2).Furthermore,AIMP1 promoted osteoclast differentiation by activating nuclear factor of activated T cells c1(NFATc1)in vitro.In contrast,exosome-coated small interfering RNA of AIMP1 effectively suppressed MM progression and osteoclast differentiation in vitro and in vivo.Conclusions:Our data demonstrate that AIMP1 is a novel regulator of histone H3 acetylation interacting with ANP32A in MM,which accelerates MM malignancy via activation of the MAPK signaling pathway.展开更多
基金National Natural Science Foundation of China,Grant/Award Number:82173849Natural Science Foundation of Jiangsu Province,Grant/Award Number:BK20200097+1 种基金Priority Academic Program Development of Jiangsu Higher Education InstitutionsJiangsu Postgraduate Research and Practice Innovation Program,Grant/Award Numbers:KYCX21_1769,KYCX20_1451。
文摘Background:Multiple myeloma(MM)is the second most common hematological malignancy.An overwhelming majority of patients with MM progress to serious osteolytic bone disease.Aminoacyl-tRNA synthetase-interacting multifunctional protein 1(AIMP1)participates in several steps during cancer development and osteoclast differentiation.This study aimed to explore its role in MM.Methods:The gene expression profiling cohorts of MM were applied to determine the expression of AIMP1 and its association with MM patient prognosis.Enzyme-linked immunosorbent assay,immunohistochemistry,and Western blotting were used to detect AIMP1 expression.Protein chip analysis,RNA-sequencing,and chromatin immunoprecipitation and next-generation sequencing were employed to screen the interacting proteins and key downstream targets of AIMP1.The impact of AIMP1 on cellular proliferation was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)assay in vitro and a xenograft model in vivo.Bone lesions were evaluated using tartrate-resistant acid phosphatase staining in vitro.A NOD/SCID-TIBIA mouse model was used to evaluate the effect of siAIMP1-loaded exosomes on bone lesion formation in vivo.Results:AIMP1 expression was increased in MM patients and strongly associated with unfavorable outcomes.Increased AIMP1 expression promoted MM cell proliferation in vitro and in vivo via activation of the mitogen-activated protein kinase(MAPK)signaling pathway.Protein chip assays and subsequent experiments revealed that AIMP1 interacted with acidic leucine-rich nuclear phosphoprotein 32 family member A(ANP32A)to regulate histone H3 acetylation.In addition,AIMP1 increased histone H3 acetylation enrichment function of GRB2-associated and regulator of MAPK protein 2(GAREM2)to increase the phosphorylation of extracellular-regulated kinase 1/2(p-ERK1/2).Furthermore,AIMP1 promoted osteoclast differentiation by activating nuclear factor of activated T cells c1(NFATc1)in vitro.In contrast,exosome-coated small interfering RNA of AIMP1 effectively suppressed MM progression and osteoclast differentiation in vitro and in vivo.Conclusions:Our data demonstrate that AIMP1 is a novel regulator of histone H3 acetylation interacting with ANP32A in MM,which accelerates MM malignancy via activation of the MAPK signaling pathway.
