Although therapeutic targets have been developed forcolorectalcancer (CRC) therapy, the therapeutic effects are not ideal and thesurvival rate for CRC patients remains poor. Therefore, it is crucialto recognize a specific target and develop an efficacious deliverysystem for CRC therapy. Herein, we demonstrate that reduced ALKBH5mediates aberrant m(6)A modification and tumor progressionin CRC. Mechanically, histone deacetylase 2-mediated H3K27 deacetylationinhibits ALKBH5 transcription in CRC, whereas ectopic ALKBH5 expressiondecreases tumorigenesis of CRC cells and protects mice from colitis-associatedtumor development. Further, METTL14/ALKBH5/IGF2BPs combine to modulateJMJD8 stability in an m(6)A-dependent manner, which increasesglycolysis and accelerates the development of CRC by enhancing theenzymatic activity of PKM2. Moreover, ALKBH5 mRNA-loaded folic acid-modifiedexosome-liposome hybrid nanoparticles were synthesized andsignificantly inhibit the progression of CRC in preclinical tumormodels by modulating the ALKBH5/JMJD8/PKM2 axis and inhibiting glycolysis.Overall, our research confirms the crucial function of ALKBH5 in regulatingthe m(6)A status in CRC and provides a direct preclinicalapproach for using ALKBH5 mRNA nanotherapeutics for CRC.

Therapeutic m(6)A eraser ALKBH5 mRNA-loaded exosome-liposome hybrid nanoparticles inhibit progression of colorectal cancer in preclinical tumor models / Wu, S; Yun, J; Tang, W; Familiari, G; Relucenti, M; Wu, J; Li, X; Chen, H; Chen, R. - In: ACS NANO. - ISSN 1936-0851. - 17:12(2023), pp. 11838-11854. [10.1021/acsnano.3c03050]

Therapeutic m(6)A eraser ALKBH5 mRNA-loaded exosome-liposome hybrid nanoparticles inhibit progression of colorectal cancer in preclinical tumor models

Familiari, G;Relucenti, M;
2023

Abstract

Although therapeutic targets have been developed forcolorectalcancer (CRC) therapy, the therapeutic effects are not ideal and thesurvival rate for CRC patients remains poor. Therefore, it is crucialto recognize a specific target and develop an efficacious deliverysystem for CRC therapy. Herein, we demonstrate that reduced ALKBH5mediates aberrant m(6)A modification and tumor progressionin CRC. Mechanically, histone deacetylase 2-mediated H3K27 deacetylationinhibits ALKBH5 transcription in CRC, whereas ectopic ALKBH5 expressiondecreases tumorigenesis of CRC cells and protects mice from colitis-associatedtumor development. Further, METTL14/ALKBH5/IGF2BPs combine to modulateJMJD8 stability in an m(6)A-dependent manner, which increasesglycolysis and accelerates the development of CRC by enhancing theenzymatic activity of PKM2. Moreover, ALKBH5 mRNA-loaded folic acid-modifiedexosome-liposome hybrid nanoparticles were synthesized andsignificantly inhibit the progression of CRC in preclinical tumormodels by modulating the ALKBH5/JMJD8/PKM2 axis and inhibiting glycolysis.Overall, our research confirms the crucial function of ALKBH5 in regulatingthe m(6)A status in CRC and provides a direct preclinicalapproach for using ALKBH5 mRNA nanotherapeutics for CRC.
2023
CRC; exosome-liposome hybrid nanoparticles; mRNA therapeutics; RNA methylation; ALKBH5
01 Pubblicazione su rivista::01a Articolo in rivista
Therapeutic m(6)A eraser ALKBH5 mRNA-loaded exosome-liposome hybrid nanoparticles inhibit progression of colorectal cancer in preclinical tumor models / Wu, S; Yun, J; Tang, W; Familiari, G; Relucenti, M; Wu, J; Li, X; Chen, H; Chen, R. - In: ACS NANO. - ISSN 1936-0851. - 17:12(2023), pp. 11838-11854. [10.1021/acsnano.3c03050]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1684904
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