Methyltransferase Set7/9 controls PARP1 expression and regulates cisplatin response of breast cancer cells

The protein-specific methyltransferase Set7/9 is known for its ability to add methyl groups to lysine residues on many targets, including as histones H1.4, H2A, H2B, H3, and non-histone proteins such as p53, NFκB, E2F1, pRb, Hif1α, β-catenin, STAT3, and YY1 transcription factors. Set7/9 affects both the landscape of histone modifications and the functionality of the aforementioned TFs, and acts as an essential mediator of vital cellular functions, regulating tumor growth and the neoplastic transformation of normal cells. The number of studies demonstrating the determining role of Set7/9 in cancer is growing. Importantly, the effect of Set7/9 on tumor progression is ambivalent and cancer-type dependent. In this study we analyzed the potential participation of Set7/9 in the essential cellular processes in breast cancer cells and revealed that Set7/9 may be involved in DNA damage signaling and DNA repair processes. We further demonstrated that Set7/9 expression is downregulated in cancerous breast tissues and inversely correlated to PARP1 expression level. Using breast cancer cell lines of HER2-positive and triple negative subtypes we have shown that the attenuation of Set7/9 led to the stabilization of PARP1 on both mRNA and protein levels that in turn resulted in cisplatin resistance acquiring. Finally, we demonstrated that the combination of cisplatin with FDA approved PARP1 inhibitor niraparib (Zejula) has a synergistic effect with cisplatin and thereby allows to overcome cisplatin resistance of Set7/9 deficient breast cancer cells.