JARID1B expression and its function in DNA damage repair are tightly regulated by miRNAs in breast cancer.
Ivano MocaviniSimone PippaValerio LicursiPaola PaciDaniela TrisciuoglioCecilia MannironiCarlo PresuttiRodolfo NegriPublished in: Cancer science (2019)
JARID1B/KDM5B histone demethylase's mRNA is markedly overexpressed 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. However, the mechanism of 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 upregulation, showed a strong downregulation of 2 microRNAs (miRNAs), 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 overexpressing 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, 3 features previously correlated with JARID1B silencing. These results enlighten an important role of a miRNA's circuit in regulating JARID1B's activity and suggest new perspectives for epigenetic therapies.
Keyphrases
- cell proliferation
- dna damage
- dna repair
- binding protein
- breast cancer cells
- long non coding rna
- poor prognosis
- cell cycle
- oxidative stress
- gene expression
- long noncoding rna
- dna methylation
- protein protein
- pi k akt
- dna damage response
- squamous cell carcinoma
- high throughput
- electronic health record
- single cell
- big data
- cancer therapy
- young adults
- papillary thyroid
- rna seq
- childhood cancer