# A genomic locus associated with radiation resistance of oral cancer cells

> **NIH NIH R03** · UNIVERSITY OF KENTUCKY · 2020 · $76,500

## Abstract

ABSTRACT
While radiation treatment is the major adjuvant therapy for patients with advanced stages of oral squamous
cell carcinoma (OSCC), the acquired resistance of OSCC cells against ionizing radiation (IR) reduces its
efficacy. It was reported that cancer stem-like cells (CSLCs) were more resistant to IR than other cells, but
the mechanism by which CSLCs acquire IR resistance remains elusive. A crucial CSLC factor that drives IR
resistance needs to be characterized, as studies have failed to observe IR resistance of cells with known
CSLC markers such as CD133 and CD44.
 Recent evidence indicates that PRMT5 (protein arginine methyl transferase 5) is crucial not only for
maintaining CSLC status, but also for enhancing DNA double-strand break repair (DSBR), and thus may be
an important target to increase efficacy of IR-based therapy. However, the molecular alterations in OSCC that
increase PRMT5 expression are not known. In addition, DNA single-strand breaks (SSB) and oxidative DNA
damage are more abundantly produced by IR than DSB, but whether high PRMT5 expression is also
associated with increased repair of these lesions has not been elucidated.
 The PRMT5 gene is in chromosome 14 where APE1, a crucial repair factor for oxidative DNA damage, is
closely localized. By scrutinizing genomics data, we found that expression of PRMT5 and APE1 are highly
coordinated, which is likely caused by the local copy number variation. Furthermore, we identify high levels of
both PRMT5 and APE1 in OSCC as an important indication of poor radiotherapy outcomes. These
observations led us to the central hypothesis of this project, that the expressional co-regulation of PRMT5
and APE1 is caused by the local copy number variation in the OSCC tissues prior to radiotherapy, and levels
of these genes synergistically influence cellular sensitivity against IR. In Aim 1 of this project, we will analyze
the copy number variation (CNV) of the genomic region in OSCC tissues and the levels of PRMT5 and APE1
proteins by immunohistochemistry, to investigate whether (a) CNV at the gene level in this region occurs in
early OSCC development before radiotherapy and (b) the CNV is associated with the PRMT5 and APE1
protein levels. In Aim 2, we will elucidate whether simultaneous knockdown or inhibition of PRMT5 and APE1
effectively sensitizes OSCC cells to IR.
 The long-term goal of this project is to delineate the novel mechanism of the PRMT5-driven IR resistance
of cells by the gene level CNV, which should help us develop not only a reliable biomarker, but also a novel
strategy of synthetic lethality that effectively targets OSCC with high levels of PRMT5.

## Key facts

- **NIH application ID:** 9962565
- **Project number:** 1R03CA249111-01
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Tadahide Izumi
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $76,500
- **Award type:** 1
- **Project period:** 2020-03-03 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9962565

## Citation

> US National Institutes of Health, RePORTER application 9962565, A genomic locus associated with radiation resistance of oral cancer cells (1R03CA249111-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9962565. Licensed CC0.

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