Histone demethylases (HDMs) have a prominent role in epigenetic regulation and are emerging as potential
therapeutic cancer targets. In particular, HDMs of class 5 (KDM5) ,also known as JARID, are over-expressed in different types of cancers and have a prominent role in cancer cells proliferation and DNA damage repair. In particular, KDM5b (JARID 1B) is upregulated in 90% of human breast cancers and in aggressive forms of melanoma. In order to understand its role in cancer cells physiology, we propose:
a - To use different chemical inhibitors of KDM5 catalytic activity and to test their effects on transcriptome, cell survival and DNA damage repair in breast cancer derived cell lines.
b - To study the functional effects of two different miRNAs which, as we previously showed, target JARID 1B mRNA and significantly modulate its abundance in breast cancer cells.
c - To extend these analyses to melanoma cell lines which over-express JARID1B.
We previously showed that JARID1B over-expression in human breast cancer tissues correlates with the down-regulation of miRNAs targeting its mRNA. In human cell lines a causal relationship between the two phenomena has been demonstrated (Mocavini et al., 2018, submitted). Moreover, in MCF7 breast cancer cell line miRNAs induced JARID1B down-regulation, although not changing the level of bulk chromatin H3K4 tri-methylation. Our preliminary results suggest that inhibition of JARID HDMs activity by chemical inhibitors and/or miRNAs can cause hypersensitivity to genotoxic damage and BRCA1 derepression. These results, if confirmed, could shed light on JARID HDMs role in protecting cancer cells against genotoxic damage and open the way for possible therapeutic use of miRNAs which specifically target these enzymes and/or their specific chemical inhibitors.
We will also investigate on a plausible mechanism for the role of HDMs in DNA damage repair. Considering the emerging role of lncRNAs at the sites of DSB we will explore the influence of HDMs activity in favoring the pervasive transcription which is required for their synthesis.