Osteosarcoma is the most common primary bone sarcoma that mostly occurs in young adults. The causes of osteosarcoma are heterogeneous and still not fully understood. Identification of novel, important oncogenic factor...Osteosarcoma is the most common primary bone sarcoma that mostly occurs in young adults. The causes of osteosarcoma are heterogeneous and still not fully understood. Identification of novel, important oncogenic factors in osteosarcoma and development of better, effective therapeutic approaches are in urgent need for better treatment of osteosarcoma patients. In this study, we uncovered that the oncogene MYC is significantly upregulated in metastastic osteosarcoma samples. In addition, high MYC expression is associated with poor survival of osteosarcoma patients. Analysis of MYC targets in osteosarcoma revealed that most of the osteosarcoma super enhancer genes are bound by MYC. Treatment of osteosarcoma cells with super enhancer inhibitors THZ1 and JQ1 effectively suppresses the proliferation, migration, and invasion of osteosarcoma cells. Mechanistically,THZ1 treatment suppresses a large group of super enhancer containing MYC target genes including CDK6 and TGFB2. These findings revealed that the MYC-driven super enhancer signaling is crucial for the osteosarcoma tumorigenesis and targeting the MYC/super enhancer axis represents as a promising therapeutic strategy for treatment of osteosarcoma patients.展开更多
Estrogen-Related Receptor Alpha(ESRRA)is an orphan nuclear receptor that plays a pivotal role in regulating cellular metabolism,mitochondrial biogenesis,and energy homeostasis through transcriptional control.It has be...Estrogen-Related Receptor Alpha(ESRRA)is an orphan nuclear receptor that plays a pivotal role in regulating cellular metabolism,mitochondrial biogenesis,and energy homeostasis through transcriptional control.It has been implicated in diverse physiological processes and diseases,including cancer.However,the transcriptional programs governed by ESRRA and the underlying molecular mechanisms remain incompletely understood.Here,we demonstrate that ESRRA serves as a central regulator in orchestrating the transcriptional activation of estrogen receptorα(ERα)-occupied super enhancers(ERSEs)and cognate ERα-target genes.In parallel,ESRRA represses the expression of cytosolic RNA sensors RIG1 and MDA5,thereby attenuating type I interferon(IFN)signaling and type I IFN-stimulated genes.In terms of mechanism,ESRRA is recruited to ERSEs together with ERαin response to estrogen and their binding to ERSEs occurs in a mutually dependent manner.In contrast,ESRRA directly binds to the promoter regions of RIG1 and MDA5 to suppress their expression.Consistent with these findings,pharmacological inhibition of ESRRA using its inverse agonist XCT790 suppressed estrogen/ERα-induced gene transcription while enhancing type I IFN pathway and antitumor immunity,thereby restraining ERα-positive breast cancer cell growth both in vitro and in vivo.Combination treatment with XCT790 and endocrine therapies,including the ERαantagonist Tamoxifen or degrader Fulvestrant,produced synergistic antitumor effects.Furthermore,co-treatment with XCT790 and tamoxifen re-sensitized Tamoxifen-resistant ERα-positive breast cancer cells to Tamoxifen treatment.In addition,XCT790 treatment augmented the therapeutic efficacy of chemotherapeutic agents such as Doxorubicin in suppressing ERα-positive breast cancer cell growth both in vitro and in vivo.In summary,our findings reveal that ESRRA is a pivotal regulator of ERSEs and estrogen/ERα-target gene activation,as well as the type I IFN signaling pathway,highlighting its potential as a promising therapeutic target in ERα-positive breast cancer in the clinic.展开更多
Acute myeloid leukemia(AML)is a malignant hematological tumor with disordered oncogenes/tumor suppressor genes and limited treatments.The potent anti-cancer effects of bromodomain and extra-terminal domain(BET)inhibit...Acute myeloid leukemia(AML)is a malignant hematological tumor with disordered oncogenes/tumor suppressor genes and limited treatments.The potent anti-cancer effects of bromodomain and extra-terminal domain(BET)inhibitors,targeting the key component of super enhancers,in early clinical trials on AML patients,implies the critical role of super enhancers in AML.Here,we review the concept and characteristic of super enhancer,and then summarize the current researches about super enhancers in AML pathogenesis,diagnosis and classification,followed by illustrate the potential super enhancer-related targets and drugs,and propose the future directions of super enhancers in AML.This information provides integrated insight into the roles of super enhancers in this disease.展开更多
T-cell acute lymphoblastic leukemia(T-ALL)is a highly aggressive hematologic malignancy with a poor prognosis,despite advancements in treatment.Many patients struggle with relapse or refrac-tory disease.Investigating ...T-cell acute lymphoblastic leukemia(T-ALL)is a highly aggressive hematologic malignancy with a poor prognosis,despite advancements in treatment.Many patients struggle with relapse or refrac-tory disease.Investigating the role of the super-enhancer(SE)regulated gene ubiquitin-specific protease 20(USP20)in T-ALL could enhance targeted therapies and improve clinical outcomes.Analysis of his-tone H3 lysine 27 acetylation(H3K27ac)chromatin immunoprecipitation sequencing(ChIP-seq)data from six T-ALL cell lines and seven pediatric samples identified USP20 as an SE-regulated driver gene.Utilizing the Cancer Cell Line Encyclopedia(CCLE)and BloodSpot databases,it was found that USP20 is specifically highly expressed in T-ALL.Knocking down USP20 with short hairpin RNA(shRNA)increased apoptosis and inhibited proliferation in T-ALL cells.In vivo studies showed that USP20 knock-down reduced tumor growth and improved survival.The USP20 inhibitor GSK2643943A demonstrated similar anti-tumor effects.Mass spectrometry,RNA-Seq,and immunoprecipitation revealed that USP20 interacted with hypoxia-inducible factor 1 subunit alpha(HIF1A)and stabilized it by deubiquitination.Cleavage under targets and tagmentation(CUT&Tag)results indicated that USP20 co-localized with HIF1A,jointly modulating target genes in T-ALL.This study identifies USP20 as a therapeutic target in T-ALL and suggests GSK2643943A as a potential treatment strategy.展开更多
基金supported by National Natural Science Foundation of China (81670874, 81500354, and 81772999)Shenzhen Science Foundation (JCYJ20160308104109234)
文摘Osteosarcoma is the most common primary bone sarcoma that mostly occurs in young adults. The causes of osteosarcoma are heterogeneous and still not fully understood. Identification of novel, important oncogenic factors in osteosarcoma and development of better, effective therapeutic approaches are in urgent need for better treatment of osteosarcoma patients. In this study, we uncovered that the oncogene MYC is significantly upregulated in metastastic osteosarcoma samples. In addition, high MYC expression is associated with poor survival of osteosarcoma patients. Analysis of MYC targets in osteosarcoma revealed that most of the osteosarcoma super enhancer genes are bound by MYC. Treatment of osteosarcoma cells with super enhancer inhibitors THZ1 and JQ1 effectively suppresses the proliferation, migration, and invasion of osteosarcoma cells. Mechanistically,THZ1 treatment suppresses a large group of super enhancer containing MYC target genes including CDK6 and TGFB2. These findings revealed that the MYC-driven super enhancer signaling is crucial for the osteosarcoma tumorigenesis and targeting the MYC/super enhancer axis represents as a promising therapeutic strategy for treatment of osteosarcoma patients.
基金supported by the National Natural Science Foundation of China(82125028,U22A20320,31871319,91953114,and 82303108)the Ministry of Science and Technology of China(2020YFA0112300 and 2020YFA0803600)+1 种基金the Shenzhen Science and Technology Program(JCYJ20230807091159001)the Fundamental Research Funds for the Central University(20720190145 and 20720220003).
文摘Estrogen-Related Receptor Alpha(ESRRA)is an orphan nuclear receptor that plays a pivotal role in regulating cellular metabolism,mitochondrial biogenesis,and energy homeostasis through transcriptional control.It has been implicated in diverse physiological processes and diseases,including cancer.However,the transcriptional programs governed by ESRRA and the underlying molecular mechanisms remain incompletely understood.Here,we demonstrate that ESRRA serves as a central regulator in orchestrating the transcriptional activation of estrogen receptorα(ERα)-occupied super enhancers(ERSEs)and cognate ERα-target genes.In parallel,ESRRA represses the expression of cytosolic RNA sensors RIG1 and MDA5,thereby attenuating type I interferon(IFN)signaling and type I IFN-stimulated genes.In terms of mechanism,ESRRA is recruited to ERSEs together with ERαin response to estrogen and their binding to ERSEs occurs in a mutually dependent manner.In contrast,ESRRA directly binds to the promoter regions of RIG1 and MDA5 to suppress their expression.Consistent with these findings,pharmacological inhibition of ESRRA using its inverse agonist XCT790 suppressed estrogen/ERα-induced gene transcription while enhancing type I IFN pathway and antitumor immunity,thereby restraining ERα-positive breast cancer cell growth both in vitro and in vivo.Combination treatment with XCT790 and endocrine therapies,including the ERαantagonist Tamoxifen or degrader Fulvestrant,produced synergistic antitumor effects.Furthermore,co-treatment with XCT790 and tamoxifen re-sensitized Tamoxifen-resistant ERα-positive breast cancer cells to Tamoxifen treatment.In addition,XCT790 treatment augmented the therapeutic efficacy of chemotherapeutic agents such as Doxorubicin in suppressing ERα-positive breast cancer cell growth both in vitro and in vivo.In summary,our findings reveal that ESRRA is a pivotal regulator of ERSEs and estrogen/ERα-target gene activation,as well as the type I IFN signaling pathway,highlighting its potential as a promising therapeutic target in ERα-positive breast cancer in the clinic.
基金This work was partially supported by the Natural Science Foundation of China(No.82070167,81870126,and 81802803).
文摘Acute myeloid leukemia(AML)is a malignant hematological tumor with disordered oncogenes/tumor suppressor genes and limited treatments.The potent anti-cancer effects of bromodomain and extra-terminal domain(BET)inhibitors,targeting the key component of super enhancers,in early clinical trials on AML patients,implies the critical role of super enhancers in AML.Here,we review the concept and characteristic of super enhancer,and then summarize the current researches about super enhancers in AML pathogenesis,diagnosis and classification,followed by illustrate the potential super enhancer-related targets and drugs,and propose the future directions of super enhancers in AML.This information provides integrated insight into the roles of super enhancers in this disease.
基金supported by grants from the National Key R&D Program of China(2022YFC2502700)National Natural Science Foundation(82072767,82141110,82172840,82203442,82300182,and 82373414,China)+5 种基金Natural Science Foundation of Jiangsu Province(BK20220047,China)Jiangsu Province’s Science and Technology Support Program(Social Development)project(BE2021657 and BE2022732,China)Suzhou Health Talent Training Project(GSWS2020047,GSWS2021028 and GSWS2022062,China)the Science and Technology Development Project of Suzhou City(SKY2022170 and SKY2023192,China)Jiangsu Provincial Health Commission Scientific Research Project(Z2022031,M2022102,ZD2022056 and H2023106,China)Medical Research Project of Jiangsu Provincial Health and Family Planning Commission(Key Project ZD2021006,China)and National Outstanding Youth Cultivation Program Project(YYJQ004,China).
文摘T-cell acute lymphoblastic leukemia(T-ALL)is a highly aggressive hematologic malignancy with a poor prognosis,despite advancements in treatment.Many patients struggle with relapse or refrac-tory disease.Investigating the role of the super-enhancer(SE)regulated gene ubiquitin-specific protease 20(USP20)in T-ALL could enhance targeted therapies and improve clinical outcomes.Analysis of his-tone H3 lysine 27 acetylation(H3K27ac)chromatin immunoprecipitation sequencing(ChIP-seq)data from six T-ALL cell lines and seven pediatric samples identified USP20 as an SE-regulated driver gene.Utilizing the Cancer Cell Line Encyclopedia(CCLE)and BloodSpot databases,it was found that USP20 is specifically highly expressed in T-ALL.Knocking down USP20 with short hairpin RNA(shRNA)increased apoptosis and inhibited proliferation in T-ALL cells.In vivo studies showed that USP20 knock-down reduced tumor growth and improved survival.The USP20 inhibitor GSK2643943A demonstrated similar anti-tumor effects.Mass spectrometry,RNA-Seq,and immunoprecipitation revealed that USP20 interacted with hypoxia-inducible factor 1 subunit alpha(HIF1A)and stabilized it by deubiquitination.Cleavage under targets and tagmentation(CUT&Tag)results indicated that USP20 co-localized with HIF1A,jointly modulating target genes in T-ALL.This study identifies USP20 as a therapeutic target in T-ALL and suggests GSK2643943A as a potential treatment strategy.
