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Inhibition of miR-1193 leads to synthetic lethality in Glioblastoma multiforme cells deficient of DNA-PKcs

Glioblastoma multiforme (GBM) is the most malignant primary brain tumor and has the highest mortality rate among cancers and high resistance to radiation and cytotoxic chemotherapy. Although some targeted therapies can partially inhibit oncogenic mutation-driven proliferation of GBM cells, therapies harnessing synthetic lethality are ‘coincidental’ treatments with high effectiveness in cancers with gene mutations, such as GBM, which frequently exhibits DNA-PKcs mutation. We provides a novel and promising therapeutic intervention strategy for DNA-PKcs-deficient GBM.
Recently, Professor Zhigang Guo’s team published their findings in the online journal of
Cell Death & Disease (https://www.nature.com/articles/s41419-020-02812-3)

By implementing a highly efficient high-throughput screening (HTS) platform using an in-house-constructed genome-wide human microRNA inhibitor library, we demonstrated that miR-1193 inhibition sensitized GBM tumor cells with DNA-PKcs deficiency. Furthermore, we found that miR-1193 directly targets YY1AP1, leading to subsequent inhibition of FEN1, an important factor in DNA damage repair. Inhibition of miR-1193 resulted in accumulation of DNA double-strand breaks and thus increased genomic instability. RPA-coated ssDNA structures enhanced ATR checkpoint kinase activity, subsequently activating the CHK1/p53/apoptosis axis. These data provide a preclinical theory for the application of miR-1193 inhibition as a potential synthetic lethal approach targeting GBM cancer cells with DNA-PKcs deficiency.
The first author is Jing Zhang, the postdoc in College of Life Sciences. Professor Jianping Liu and Professor Zhigang Guo are the co-corresponding authors.