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Set7/9 controls proliferation and genotoxic drug resistance of NSCLC cells

Set7/9 controls proliferation and genotoxic drug resistance of NSCLC cells

Authors :
Alena Kizenko
Victoria Mamontova
Sergey Parfenyev
Olga A. Fedorova
Nickolai A. Barlev
Alexandra Daks
Aigul R. Venina
Oleg Shuvalov
Alexey Petukhov
Sofia Netsvetay
Evgeny N. Imyanitov
Source :
Biochemical and Biophysical Research Communications. 572:41-48
Publication Year :
2021
Publisher :
Elsevier BV, 2021.

Abstract

The SET domain containing lysine-specific methyltransferase, Set7/9, covalently attaches methyl moieties to a variety of histone and non-histone substrates. Among the substrates of Set7/9 are: p53, NF-kB, PARP1, E2F1, and other transcription factors that regulate many vital processes in the cell. Through the post-translational regulation of these critical master-regulators Set7/9 is involved in regulation of cell proliferation, cancer progression, and DNA damage response. Noteworthy, the role of Set7/9 in tumorigenesis is contradictory and apparently depends on the cellular context. In this study, we investigated the effect of Set7/9 on tumorigenic characteristics of lung cancer cells. We showed that CRISPR/Cas9-mediated knock-out of Set7/9 in A549 and its shRNA-mediated knock-down in H1299 NSCLC cell lines both augment the proliferation rate of tumor cells compared to the matching wild-type cells. Mechanistically, ablation of Set7/9 increased the expression of cyclin A2 and D1 genes thereby promoting the accumulation of cells in S phase. Furthermore, knockout of Set7/9 decreased the expression of E-cadherin, whose product is critical for cell-cell interactions. Accordingly, this led to the increased migration of lung cancer cells. Finally, both ablation or pharmacological inhibition of Set7/9 enzymatic methyltransferase activity by the selective inhibitor (R)-PFI-2 sensitized NSCLC cells to genotoxic drug, doxorubicin. This effect was also recapitulated on patients-derived NSCLC cell lines. Taken together, our results suggest that Set7/9 plays anti-proliferative and DNA damage-protective roles in NSCLC cells and hence represents an attractive target for anti-cancer chemotherapy.

Details

ISSN :
0006291X
Volume :
572
Database :
OpenAIRE
Journal :
Biochemical and Biophysical Research Communications
Accession number :
edsair.doi.dedup.....fbb241844d00e77207d9208d5d05c3e0
Full Text :
https://doi.org/10.1016/j.bbrc.2021.07.086