Gene expression is finely controlled by the abundance and activation status of transcription factors and their regulators,as well as by a number of reversible modifications of DNA and histones that are commonly referr...Gene expression is finely controlled by the abundance and activation status of transcription factors and their regulators,as well as by a number of reversible modifications of DNA and histones that are commonly referred to as epigenetic marks.Such alterations(i.e.,methylation,acetylation,and ubiquitination)are catalyzed by an array of dedicated enzymes with antagonistic activity,including methyltransferases and demethylases,acetyltransferases and deacetylases,as well as ubiquitin ligases and deubiquitinating enzymes.The epigenetic control of transcription is critical not only for embryonic and postembryonic development but also for the preservation of homeostasis in all adult tissues.In line with this notion,epigenetic defects have been associated with a variety of human disorders,including(but not limited to)congenital conditions as well as multiple hematological and solid tumors.Here,we provide an in-depth discussion of the impact of epigenetic alterations on cancer stemness,i.e.,the ability of a small population of poorly differentiated malignant cells to(1)self-renew while generating a more differentiated progeny,and(2)exhibit superior tumor initiating/repopulating potential along with exceptional plasticity and improved resistance to environmental and therapy-elicited stress.Moreover,we critically evaluate the potential and limitations of targeting epigenetic modifiers as a means to eradicate cancer stem cells for therapeutic purposes.展开更多
基金supported by a fellowship from the American Italian Cancer Foundation(AICF)(#223565-01)supported by the Italian Ministry of Health,Ricerca Finalizzata 2021 Giovani Ricercatori,ID.GR-2021-12375316+19 种基金funded by the CERCA Program/Generalitat de Catalunya,MCIN/AEI/10.13039/501100011033the European Development Regional Fund,“A way to make Europe”EDRF(project PID2021-125282OB-I00)Departament de Recerca i Universitats/Generalitat de Catalunya(2021 SGR 01494)“La Caixa”Research Foundation and the Cellex Foundation(CEL007)supported(as a PI unless otherwise indicated)by one NIH R01 grant(#CA271915)by two Breakthrough Level 2 grants from the US DoD BCRP(#BC180476P1,#BC210945)by a grant from the STARR Cancer Consortium(#I16--0064)by a Transformative Breast Cancer Consortium Grant from the US DoD BCRP(#W81XWH2120034,PI:Formenti)by a U54 grant from NIH/NCI(#CA274291,PI:Deasy,Formenti,Weichselbaum)by the 2019 Laura Ziskin Prize in Translational Research(#ZP--6177,PI:Formenti)from the Stand Up to Cancer(SU2C)by a Mantle Cell Lymphoma Research Initiative(MCL-RI,PI:Chen-Kiang)grant from the Leukemia and Lymphoma Society(LLS)by a Rapid Response Grant from the Functional Genomics Initiative(New York,US)by a pre-SPORE grant(PI:Demaria,Formenti),a Collaborative Research Initiative Grant and a Clinical Trials Innovation Grant from the Sandra and Edward Meyer Cancer Center(New York,US)by startup funds from the Dept.of Radiation Oncology at Weill Cornell Medicine(New York,US)by startup funds from Fox Chase Cancer Center(Philadelphia,US)by donations from Promontory(New York,US)the Luke Heller TECPR2 Foundation(Boston,US),supported by funding from Associazione Italiana per la Ricerca sul Cancro AIRC,IG 2022 ID.27685CARESS Fondazione Piemontese per la Ricerca sul Cancro(FRPC)5×1000 Intramural Grantthe European Union–Next Generation EU–PNRR M6C2-Investimento 2.1 Valorizzazione e potenziamento della ricerca biomedica del SSN(ID.PNRR-POC-2023-12378288)funds from the Italian Institute for Genomic Medicine and Compagnia di San Paolo.
文摘Gene expression is finely controlled by the abundance and activation status of transcription factors and their regulators,as well as by a number of reversible modifications of DNA and histones that are commonly referred to as epigenetic marks.Such alterations(i.e.,methylation,acetylation,and ubiquitination)are catalyzed by an array of dedicated enzymes with antagonistic activity,including methyltransferases and demethylases,acetyltransferases and deacetylases,as well as ubiquitin ligases and deubiquitinating enzymes.The epigenetic control of transcription is critical not only for embryonic and postembryonic development but also for the preservation of homeostasis in all adult tissues.In line with this notion,epigenetic defects have been associated with a variety of human disorders,including(but not limited to)congenital conditions as well as multiple hematological and solid tumors.Here,we provide an in-depth discussion of the impact of epigenetic alterations on cancer stemness,i.e.,the ability of a small population of poorly differentiated malignant cells to(1)self-renew while generating a more differentiated progeny,and(2)exhibit superior tumor initiating/repopulating potential along with exceptional plasticity and improved resistance to environmental and therapy-elicited stress.Moreover,we critically evaluate the potential and limitations of targeting epigenetic modifiers as a means to eradicate cancer stem cells for therapeutic purposes.
