Loss of Mediator complex subunit 13 (MED13) promotes resistance to alkylation through cyclin D1 upregulation.

Autor:	Roliński M; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7049 Trondheim, Norway., Montaldo NP; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7049 Trondheim, Norway., Aksu ME; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7049 Trondheim, Norway., Fordyce Martin SL; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7049 Trondheim, Norway., Brambilla A; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7049 Trondheim, Norway., Kunath N; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7049 Trondheim, Norway., Johansen J; Bioinformatics core facility - BioCore; Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway., Erlandsen SE; Genomics core facility, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway., Liabbak NB; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7049 Trondheim, Norway., Rian K; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7049 Trondheim, Norway., Bjørås M; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7049 Trondheim, Norway.; Department of Microbiology, Oslo University Hospital, 0027 Oslo, Norway; Department of Medical Biochemistry, Oslo University Hospital and University of Oslo, 0372 Oslo, Norway., Sætrom P; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7049 Trondheim, Norway.; Bioinformatics core facility - BioCore; Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway.; K.G. Jebsen Center for Genetic Epidemiology, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway.; Department of Computer Science, Faculty of Information Technology and Electrical Engineering, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway., van Loon B; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7049 Trondheim, Norway.
Jazyk:	angličtina
Zdroj:	Nucleic acids research [Nucleic Acids Res] 2021 Feb 22; Vol. 49 (3), pp. 1470-1484.
DOI:	10.1093/nar/gkaa1289
Abstrakt:	Alkylating drugs are among the most often used chemotherapeutics. While cancer cells frequently develop resistance to alkylation treatments, detailed understanding of mechanisms that lead to the resistance is limited. Here, by using genome-wide CRISPR-Cas9 based screen, we identify transcriptional Mediator complex subunit 13 (MED13) as a novel modulator of alkylation response. The alkylation exposure causes significant MED13 downregulation, while complete loss of MED13 results in reduced apoptosis and resistance to alkylating agents. Transcriptome analysis identified cyclin D1 (CCND1) as one of the highly overexpressed genes in MED13 knock-out (KO) cells, characterized by shorter G1 phase. MED13 is able to bind to CCND1 regulatory elements thus influencing the expression. The resistance of MED13 KO cells is directly dependent on the cyclin D1 overexpression, and its down-regulation is sufficient to re-sensitize the cells to alkylating agents. We further demonstrate the therapeutic potential of MED13-mediated response, by applying combinatory treatment with CDK8/19 inhibitor Senexin A. Importantly, the treatment with Senexin A stabilizes MED13, and in combination with alkylating agents significantly reduces viability of cancer cells. In summary, our findings identify novel alkylation stress response mechanism dependent on MED13 and cyclin D1 that can serve as basis for development of innovative therapeutic strategies. (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Databáze:	MEDLINE
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