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
Apolipoprotein A-I(Apo A-I),the main protein component of high-density lipoprotein(HDL),plays a pivotal role in reverse cholesterol transport(RCT).Previous studies indicated a reduction of serum Apo A-I levels in vari...Apolipoprotein A-I(Apo A-I),the main protein component of high-density lipoprotein(HDL),plays a pivotal role in reverse cholesterol transport(RCT).Previous studies indicated a reduction of serum Apo A-I levels in various types of cancer,suggesting Apo A-I as a potential cancer biomarker.Herein,ectopically overexpressed Apo A-I in MDA-MB-231 breast cancer cells was observed to have antitumor effects,inhibiting cell proliferation and migration.Subsequent studies on the mechanism of expression regulation revealed that estradiol(E2)/estrogen receptorα(ERα)signaling activates Apo A-I gene transcription in breast cancer cells.Mechanistically,our Ch IP-seq data showed that ERαdirectly binds to the estrogen response element(ERE)site within the Apo A-I gene and establishes an acetylation of histone 3 lysine 27(H3 K27 ac)-enriched chromatin microenvironment.Conversely,Fulvestrant(ICI 182780)treatment blocked ERαbinding to ERE within the Apo A-I gene and downregulated the H3 K27 ac level on the Apo A-I gene.Treatment with p300 inhibitor also significantly decreased the Apo A-I messenger RNA(m RNA)level in MCF7 cells.Furthermore,the analysis of data from The Cancer Genome Atlas(TCGA)revealed a positive correlation between ERαand Apo A-I expression in breast cancer tissues.Taken together,our study not only revealed the antitumor potential of Apo A-I at the cellular level,but also found that ERαpromotes the transcription of Apo A-I gene through direct genomic effects,and p300 may act as a co-activator of ERαin this process.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.
基金supported by the National Natural Science Foundation of China(Nos.81672785,31871291,and82073113 to Li TAN)the National Key R&D Project of China(No.2016YFA0101800 to Li TAN)supported by the Innovative Research Team of High-level Local University in Shanghai。
文摘Apolipoprotein A-I(Apo A-I),the main protein component of high-density lipoprotein(HDL),plays a pivotal role in reverse cholesterol transport(RCT).Previous studies indicated a reduction of serum Apo A-I levels in various types of cancer,suggesting Apo A-I as a potential cancer biomarker.Herein,ectopically overexpressed Apo A-I in MDA-MB-231 breast cancer cells was observed to have antitumor effects,inhibiting cell proliferation and migration.Subsequent studies on the mechanism of expression regulation revealed that estradiol(E2)/estrogen receptorα(ERα)signaling activates Apo A-I gene transcription in breast cancer cells.Mechanistically,our Ch IP-seq data showed that ERαdirectly binds to the estrogen response element(ERE)site within the Apo A-I gene and establishes an acetylation of histone 3 lysine 27(H3 K27 ac)-enriched chromatin microenvironment.Conversely,Fulvestrant(ICI 182780)treatment blocked ERαbinding to ERE within the Apo A-I gene and downregulated the H3 K27 ac level on the Apo A-I gene.Treatment with p300 inhibitor also significantly decreased the Apo A-I messenger RNA(m RNA)level in MCF7 cells.Furthermore,the analysis of data from The Cancer Genome Atlas(TCGA)revealed a positive correlation between ERαand Apo A-I expression in breast cancer tissues.Taken together,our study not only revealed the antitumor potential of Apo A-I at the cellular level,but also found that ERαpromotes the transcription of Apo A-I gene through direct genomic effects,and p300 may act as a co-activator of ERαin this process.