Abstract

Genome instability in cancer cells causes not only point mutations but also structural variations of the genome, including copy number variations (CNVs). It has recently been proposed that CNVs arise in cancer to adapt to a given microenvironment to survive. However, how CNV influences cellular resistance against ionizing radiation remains unknown. PRMT5 (protein arginine methyltransferase 5) and APE1 (apurinic/apyrimidinic endonuclease 1), which enhance repair of DNA double-strand breaks and oxidative DNA damage, are closely localized in the chromosome 14 of the human genome. In this study, the genomics data for the PRMT5 and APE1 genes, including their expression, CNVs, and clinical outcomes, were analyzed using TCGA’s data set for oral squamous cell carcinoma patients. The two genes were found to share almost identical CNV values among cancer tissues from oral squamous cell carcinoma (OSCC) patients. Levels of expression of PRMT5 and APE1 in OSCC tissues are highly correlated in cancer but not in normal tissues, suggesting that regulation of PRMT5 and APE1 were overridden by the extent of CNV in the PRMT5-APE1 genome region. High expression levels of PRMT5 and APE1 were both associated with poor survival outcomes after radiation therapy. Simultaneous down-regulation of PRMT5 and APE1 synergistically hampered DNA double-strand break repair and sensitized OSCC cell lines to X-ray irradiation in vitro and in vivo. These results suggest that the extent of CNV in a particular genome region significantly influence the radiation resistance of cancer cells. Profiling CNV in the PRMT5-APE1 genome region may help us to understand the mechanism of the acquired radioresistance of tumor cells, and raises the possibility that simultaneous inhibition of PRMT5 and APE1 may increase the efficacy of radiation therapy.

Original languageEnglish
Article number2425
JournalCells
Volume12
Issue number20
DOIs
StatePublished - Oct 2023

Bibliographical note

Publisher Copyright:
© 2023 by the authors.

Funding

This research was funded by the National Cancer Institute (R03CA249111, T.I.). The Markey Cancer Center Shared Resource Facilities are supported by P30CA177558.

FundersFunder number
National Childhood Cancer Registry – National Cancer InstituteP30CA177558, R03CA249111
National Childhood Cancer Registry – National Cancer Institute

    Keywords

    • DNA repair
    • copy number variation
    • genome instability
    • oral squamous cell carcinoma
    • radiation resistance

    ASJC Scopus subject areas

    • General Biochemistry, Genetics and Molecular Biology

    Fingerprint

    Dive into the research topics of 'Copy Number Variation That Influences the Ionizing Radiation Sensitivity of Oral Squamous Cell Carcinoma'. Together they form a unique fingerprint.

    Cite this