JARID1B/KDM5B histone demethylase's mRNA is markedly over-expressed in breast cancer tissues and cell lines and the protein has been shown to have a prominent role in cancer cell proliferation and DNA repair. On the other hand, its post-transcriptional regulation in cancer cells remains elusive. We performed a computational analysis of transcriptomic data from a set of 103 breast cancer patients which, along with JARID1B up-regulation, showed a strong down-regulation of two miRNA, mir-381 and mir-486, potentially targeting its mRNA. We showed that both miRNAs can target JARID1B 3'UTR and reduce luciferase's activity in a complementarity-driven repression assay. Moreover, MCF7 breast cancer cells over-expressing JARID1B showed a strong protein reduction when transfected with mir-486. This protein's decrease is accompanied by accumulation of DNA damage, enhanced radiosensitivity and increase of BRCA1 mRNA, three features previously correlated with JARID1B silencing. These results enlighten an important role of a miRNAs' circuit in regulating JARID1B's activity and suggest new perspectives for epigenetic therapies. This article is protected by copyright. All rights reserved.
JARID1B expression and its function in DNA damage repair are tightly regulated by miRNAs in breast cancer
Licursi V;Paci P;Trisciuoglio D;Mannironi C;
2019
Abstract
JARID1B/KDM5B histone demethylase's mRNA is markedly over-expressed in breast cancer tissues and cell lines and the protein has been shown to have a prominent role in cancer cell proliferation and DNA repair. On the other hand, its post-transcriptional regulation in cancer cells remains elusive. We performed a computational analysis of transcriptomic data from a set of 103 breast cancer patients which, along with JARID1B up-regulation, showed a strong down-regulation of two miRNA, mir-381 and mir-486, potentially targeting its mRNA. We showed that both miRNAs can target JARID1B 3'UTR and reduce luciferase's activity in a complementarity-driven repression assay. Moreover, MCF7 breast cancer cells over-expressing JARID1B showed a strong protein reduction when transfected with mir-486. This protein's decrease is accompanied by accumulation of DNA damage, enhanced radiosensitivity and increase of BRCA1 mRNA, three features previously correlated with JARID1B silencing. These results enlighten an important role of a miRNAs' circuit in regulating JARID1B's activity and suggest new perspectives for epigenetic therapies. This article is protected by copyright. All rights reserved.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
