Bone undergoes a constant and continuous remodeling process that is tightly regulated by the coordinated and sequential actions of bone-resorbing osteoclasts and bone-forming osteoblasts.Recent studies have shown that...Bone undergoes a constant and continuous remodeling process that is tightly regulated by the coordinated and sequential actions of bone-resorbing osteoclasts and bone-forming osteoblasts.Recent studies have shown that histone demethylases are implicated in osteoblastogenesis;however,little is known about the role of histone demethylases in osteoclast formation.Here,we identified KDM4B as an epigenetic regulator of osteoclast differentiation.Knockdown of KDM4B significantly blocked the formation of tartrate-resistant acid phosphatase-positive multinucleated cells.Mice with myeloid-specific conditional knockout of KDM4B showed an osteopetrotic phenotype due to osteoclast deficiency.Biochemical analysis revealed that KDM4B physically and functionally associates with CCAR1 and MED1 in a complex.Using genome-wide chromatin immunoprecipitation(ChIP)-sequencing,we revealed that the KDM4B–CCAR1–MED1 complex is localized to the promoters of several osteoclast-related genes upon receptor activator of NF-κB ligand stimulation.We demonstrated that the KDM4B–CCAR1–MED1 signaling axis induces changes in chromatin structure(euchromatinization)near the promoters of osteoclast-related genes through H3K9 demethylation,leading to NF-κB p65 recruitment via a direct interaction between KDM4B and p65.Finally,small molecule inhibition of KDM4B activity impeded bone loss in an ovariectomized mouse model.Taken together,our findings establish KDM4B as a critical regulator of osteoclastogenesis,providing a potential therapeutic target for osteoporosis.展开更多
Breast cancer,one of the most frequent cancer types,is a leading cause of death in women worldwide.Estrogen receptor(ER)αis a nuclear hormone receptor that plays key roles in mammary gland development and breast canc...Breast cancer,one of the most frequent cancer types,is a leading cause of death in women worldwide.Estrogen receptor(ER)αis a nuclear hormone receptor that plays key roles in mammary gland development and breast cancer.About 75%of breast cancer cases are diagnosed as ER-positive;however,nearly half of these cancers are either intrinsically or inherently resistant to the current anti-estrogen therapies.Recent studies have identified an ER coactivator,Mediator Subunit 1(MED1),as a unique,tissue-specific cofactor that mediates breast cancer metastasis and treatment resistance.MED1 is overexpressed in over 50%of human breast cancer cases and co-amplifies with another important breast cancer gene,receptor tyrosine kinase HER2.Clinically,MED1 expression highly correlates with poor disease-free survival of breast cancer patients,and recent studies have reported an increased frequency of MED1 mutations in the circulating tumor cells of patients after treatment.In this review,we discuss the biochemical characterization of MED1 and its associated MED1/Mediator complex,its crosstalk with HER2 in anti-estrogen resistance,breast cancer stem cell formation,and metastasis both in vitro and in vivo.Furthermore,we elaborate on the current advancements in targeting MED1 using state-of-the-art RNA nanotechnology and discuss the future perspectives as well.展开更多
Breast cancer is one of the most common cancer and leading causes of death in women in the United States and Worldwide.About 90%of breast cancers belong to ER+or HER2+subtypes and are driven by key breast cancer genes...Breast cancer is one of the most common cancer and leading causes of death in women in the United States and Worldwide.About 90%of breast cancers belong to ER+or HER2+subtypes and are driven by key breast cancer genes Estrogen Receptor and HER2,respectively.Despite the advances in anti-estrogen(endocrine)and anti-HER2 therapies for the treatment of these breast cancer subtypes,unwanted side effects,frequent recurrence and resistance to these treatments remain major clinical challenges.Recent studies have identified ER coactivator MED1 as a key mediator of ER functions and anti-estrogen treatment resistance.Interestingly,MED1 is also coamplified with HER2 and activated by the HER2 signaling cascade,and plays critical roles in HER2-mediated tumorigenesis and response to anti-HER2 treatment as well.Thus,MED1 represents a novel crosstalk point of the HER2 and ER pathways and a highly promising new therapeutic target for ER+and HER2+breast cancer treatment.In this review,we will discuss the recent progress on the role of this key ER/HER2 downstream effector MED1 in breast cancer therapy resistance and our development of an innovative RNA nanotechnology-based approach to target MED1 for potential future breast cancer therapy to overcome treatment resistance.展开更多
The Mediator Complex plays key roles in activating gene transcription in eukaryotes.Mediator of RNA polymerase II transcription subunit 12 homolog(MED12)is a subunit of the Mediator Complex and regu-lates the activity...The Mediator Complex plays key roles in activating gene transcription in eukaryotes.Mediator of RNA polymerase II transcription subunit 12 homolog(MED12)is a subunit of the Mediator Complex and regu-lates the activity of the complex.MED12 is involved in a variety of cellular activities,and mutations in MED12 gene impair MED12 activities and are associated with several diseases,including Opitz-Kaveggia syndrome,Lujan syndrome,uterine leiomyomas and prostate cancer.This review will discuss the bio-logical function of MED12 and the relationship between MED12 mutations and diseases.展开更多
Background:Recent studies have shown that mediator complex subunit 1(Med1)can significantly affect hepatocyte proliferation and differentiation.Acting as a tumor suppressor,microRNA-637(hsa-miR-637)can inhibit the gro...Background:Recent studies have shown that mediator complex subunit 1(Med1)can significantly affect hepatocyte proliferation and differentiation.Acting as a tumor suppressor,microRNA-637(hsa-miR-637)can inhibit the growth of hepatocarcinoma cells and further induce cell apoptosis.However,the function of hsa-miR-637 and its target genes during liver regeneration remains to be elucidated.Methods:This study used co-immunoprecipitation(Co-IP)assay,transfection,luciferase reporter assay,functional assay by cell counting kit-8(CCK-8),Annexin V-FITC/propidium iodide apoptosis assay,and quantitative polymerase chain reaction analysis of chromatin immunoprecipitation(ChIP)for analysis.Results:Hsa-miR-637 has been suggested to suppress the expression of two Med1-interacting nuclear receptors,identified as the peroxisome proliferator-activated receptor alpha(PPARA)and thyroid hormone receptor alpha(THRA)at the transcriptional and translational levels in the human liver HL-7702 cell line.The interaction between Med1 and PPARA/THRA in HL-7702 cells was then confirmed.The transcriptional repression of hsa-miR-637 on PPARA and THRA was also demonstrated.Moreover,hsamiR-637 has been determined to suppress the proliferation of HL-7702 cells.Furthermore,cell cycle arrest of HL-7702 cells was induced by transfection of hsa-miR-637 at the S phase,but its apoptosis failed.Finally,PPARA was indicated to directly bind to the promoter of some transcription factors,like bcatenin,mouse double minute 2(MDM2),and p53.Conclusions:This study has confirmed that hsa-miR-637 plays an antiproliferative role during liver regeneration,which may contribute in understanding the regenerative process of the liver.展开更多
supported by grants from the National Basic Research Program of China （2014CB138404）;the China National Science Fund for Innovative Research Groups of Biological Control （31321063）;the National Basic Research Prog...supported by grants from the National Basic Research Program of China （2014CB138404）;the China National Science Fund for Innovative Research Groups of Biological Control （31321063）;the National Basic Research Program of China （973 Program, 2009CB119203）;the National Natural Science Foundation for Young Scientists in China （31101674）展开更多
Bemisia tabaci-transmitted geminiviruses are one of the major threats on cassava and vegetable crops in Africa. However, to date, few studies are available on the diversity orB. tabaci and their associated endosymbion...Bemisia tabaci-transmitted geminiviruses are one of the major threats on cassava and vegetable crops in Africa. However, to date, few studies are available on the diversity orB. tabaci and their associated endosymbionts in Africa. More than 28 species have been described in the complex ofB. tabaci cryptic species; among them, 2 are invasive pests worldwide： MED and MEAM1. In order to assess the species diversity orB. tabaci in vegetable crops in Senegal, several samplings in different localities, hosts and seasons were collected and analyzed with nuclear （microsatellite） and mitochondrial （COI） markers. The bacterial endosymbiont community was also studied for each sample. Two species were detected： MED Q1 and MEAM1 B. Patterns of MED Q1 （dominance on most of the samples and sites, highest nuclear and mitochondrial diversity and broader secondary endosymbiont community： Hamiltonella, Cardinium, Wolbachia and Rickettsia）, point toward a predominant resident begomovirus vector group for MED Q 1 on market gardening crops. Furthermore, the lower prevalence of the second species MEAM1 B, its lower nuclear and mitochondrial diversity and a narrower secondary endosymbiont community （Hamiltonella/Rickettsia）, indicate that this genetic group is exotic and results from a recent invasion in this area.展开更多
基金support of the National Research Foundation of Korea(2017R1C1B2008017,2020R1A6A1A06046235,and 2020R1A2C1008179 to K.K.,2019R1I1A1A01061125 to S.J.Y.).
文摘Bone undergoes a constant and continuous remodeling process that is tightly regulated by the coordinated and sequential actions of bone-resorbing osteoclasts and bone-forming osteoblasts.Recent studies have shown that histone demethylases are implicated in osteoblastogenesis;however,little is known about the role of histone demethylases in osteoclast formation.Here,we identified KDM4B as an epigenetic regulator of osteoclast differentiation.Knockdown of KDM4B significantly blocked the formation of tartrate-resistant acid phosphatase-positive multinucleated cells.Mice with myeloid-specific conditional knockout of KDM4B showed an osteopetrotic phenotype due to osteoclast deficiency.Biochemical analysis revealed that KDM4B physically and functionally associates with CCAR1 and MED1 in a complex.Using genome-wide chromatin immunoprecipitation(ChIP)-sequencing,we revealed that the KDM4B–CCAR1–MED1 complex is localized to the promoters of several osteoclast-related genes upon receptor activator of NF-κB ligand stimulation.We demonstrated that the KDM4B–CCAR1–MED1 signaling axis induces changes in chromatin structure(euchromatinization)near the promoters of osteoclast-related genes through H3K9 demethylation,leading to NF-κB p65 recruitment via a direct interaction between KDM4B and p65.Finally,small molecule inhibition of KDM4B activity impeded bone loss in an ovariectomized mouse model.Taken together,our findings establish KDM4B as a critical regulator of osteoclastogenesis,providing a potential therapeutic target for osteoporosis.
基金Project supported by the National Cancer Institute(No.R01CA197865),the Ride Cincinnati Awardthe National Center for Advancing Translation Science of the National Institutes of Health(No.UL1TR001425),USA
文摘Breast cancer,one of the most frequent cancer types,is a leading cause of death in women worldwide.Estrogen receptor(ER)αis a nuclear hormone receptor that plays key roles in mammary gland development and breast cancer.About 75%of breast cancer cases are diagnosed as ER-positive;however,nearly half of these cancers are either intrinsically or inherently resistant to the current anti-estrogen therapies.Recent studies have identified an ER coactivator,Mediator Subunit 1(MED1),as a unique,tissue-specific cofactor that mediates breast cancer metastasis and treatment resistance.MED1 is overexpressed in over 50%of human breast cancer cases and co-amplifies with another important breast cancer gene,receptor tyrosine kinase HER2.Clinically,MED1 expression highly correlates with poor disease-free survival of breast cancer patients,and recent studies have reported an increased frequency of MED1 mutations in the circulating tumor cells of patients after treatment.In this review,we discuss the biochemical characterization of MED1 and its associated MED1/Mediator complex,its crosstalk with HER2 in anti-estrogen resistance,breast cancer stem cell formation,and metastasis both in vitro and in vivo.Furthermore,we elaborate on the current advancements in targeting MED1 using state-of-the-art RNA nanotechnology and discuss the future perspectives as well.
基金This work was supported by National Cancer Institute(NCI)R01 grants(CA197865,CA229869)University of Cincinnati Cancer Center and Ride Cincinnati Award(to X.Zhang).
文摘Breast cancer is one of the most common cancer and leading causes of death in women in the United States and Worldwide.About 90%of breast cancers belong to ER+or HER2+subtypes and are driven by key breast cancer genes Estrogen Receptor and HER2,respectively.Despite the advances in anti-estrogen(endocrine)and anti-HER2 therapies for the treatment of these breast cancer subtypes,unwanted side effects,frequent recurrence and resistance to these treatments remain major clinical challenges.Recent studies have identified ER coactivator MED1 as a key mediator of ER functions and anti-estrogen treatment resistance.Interestingly,MED1 is also coamplified with HER2 and activated by the HER2 signaling cascade,and plays critical roles in HER2-mediated tumorigenesis and response to anti-HER2 treatment as well.Thus,MED1 represents a novel crosstalk point of the HER2 and ER pathways and a highly promising new therapeutic target for ER+and HER2+breast cancer treatment.In this review,we will discuss the recent progress on the role of this key ER/HER2 downstream effector MED1 in breast cancer therapy resistance and our development of an innovative RNA nanotechnology-based approach to target MED1 for potential future breast cancer therapy to overcome treatment resistance.
文摘The Mediator Complex plays key roles in activating gene transcription in eukaryotes.Mediator of RNA polymerase II transcription subunit 12 homolog(MED12)is a subunit of the Mediator Complex and regu-lates the activity of the complex.MED12 is involved in a variety of cellular activities,and mutations in MED12 gene impair MED12 activities and are associated with several diseases,including Opitz-Kaveggia syndrome,Lujan syndrome,uterine leiomyomas and prostate cancer.This review will discuss the bio-logical function of MED12 and the relationship between MED12 mutations and diseases.
基金This study was supported by the National Science and Technology Major Project of China(2018ZX10302204-002)The authors would like to thank BersinBio(Guangzhou,China)for their technical assistance.
文摘Background:Recent studies have shown that mediator complex subunit 1(Med1)can significantly affect hepatocyte proliferation and differentiation.Acting as a tumor suppressor,microRNA-637(hsa-miR-637)can inhibit the growth of hepatocarcinoma cells and further induce cell apoptosis.However,the function of hsa-miR-637 and its target genes during liver regeneration remains to be elucidated.Methods:This study used co-immunoprecipitation(Co-IP)assay,transfection,luciferase reporter assay,functional assay by cell counting kit-8(CCK-8),Annexin V-FITC/propidium iodide apoptosis assay,and quantitative polymerase chain reaction analysis of chromatin immunoprecipitation(ChIP)for analysis.Results:Hsa-miR-637 has been suggested to suppress the expression of two Med1-interacting nuclear receptors,identified as the peroxisome proliferator-activated receptor alpha(PPARA)and thyroid hormone receptor alpha(THRA)at the transcriptional and translational levels in the human liver HL-7702 cell line.The interaction between Med1 and PPARA/THRA in HL-7702 cells was then confirmed.The transcriptional repression of hsa-miR-637 on PPARA and THRA was also demonstrated.Moreover,hsamiR-637 has been determined to suppress the proliferation of HL-7702 cells.Furthermore,cell cycle arrest of HL-7702 cells was induced by transfection of hsa-miR-637 at the S phase,but its apoptosis failed.Finally,PPARA was indicated to directly bind to the promoter of some transcription factors,like bcatenin,mouse double minute 2(MDM2),and p53.Conclusions:This study has confirmed that hsa-miR-637 plays an antiproliferative role during liver regeneration,which may contribute in understanding the regenerative process of the liver.
基金supported by grants from the National Basic Research Program of China (2014CB138404)the China National Science Fund for Innovative Research Groups of Biological Control (31321063)+1 种基金the National Basic Research Program of China (973 Program, 2009CB119203)the National Natural Science Foundation for Young Scientists in China (31101674)
文摘supported by grants from the National Basic Research Program of China （2014CB138404）;the China National Science Fund for Innovative Research Groups of Biological Control （31321063）;the National Basic Research Program of China （973 Program, 2009CB119203）;the National Natural Science Foundation for Young Scientists in China （31101674）
文摘Bemisia tabaci-transmitted geminiviruses are one of the major threats on cassava and vegetable crops in Africa. However, to date, few studies are available on the diversity orB. tabaci and their associated endosymbionts in Africa. More than 28 species have been described in the complex ofB. tabaci cryptic species; among them, 2 are invasive pests worldwide： MED and MEAM1. In order to assess the species diversity orB. tabaci in vegetable crops in Senegal, several samplings in different localities, hosts and seasons were collected and analyzed with nuclear （microsatellite） and mitochondrial （COI） markers. The bacterial endosymbiont community was also studied for each sample. Two species were detected： MED Q1 and MEAM1 B. Patterns of MED Q1 （dominance on most of the samples and sites, highest nuclear and mitochondrial diversity and broader secondary endosymbiont community： Hamiltonella, Cardinium, Wolbachia and Rickettsia）, point toward a predominant resident begomovirus vector group for MED Q 1 on market gardening crops. Furthermore, the lower prevalence of the second species MEAM1 B, its lower nuclear and mitochondrial diversity and a narrower secondary endosymbiont community （Hamiltonella/Rickettsia）, indicate that this genetic group is exotic and results from a recent invasion in this area.
