ACLY (ATP Citrate Lyase) Mediates Radioresistance in Head and Neck Squamous Cell Carcinomas and is a Novel Predictive Radiotherapy Biomarker
Publication year
2019Source
Cancers, 11, 12, (2019), article 1971ISSN
Publication type
Article / Letter to editor

Display more detailsDisplay less details
Organization
Radiation Oncology
Biochemistry (UMC)
Laboratory Medicine
Journal title
Cancers
Volume
vol. 11
Issue
iss. 12
Subject
Radboudumc 17: Women's cancers RIMLS: Radboud Institute for Molecular Life Sciences; Radboudumc 19: Nanomedicine RIMLS: Radboud Institute for Molecular Life Sciences; Radboudumc 2: Cancer development and immune defence RIMLS: Radboud Institute for Molecular Life Sciences; Radboudumc 9: Rare cancers RIHS: Radboud Institute for Health SciencesAbstract
Radiotherapy is an important treatment modality of head and neck squamous cell carcinomas (HNSCC). Multiple links have been described between the metabolic activity of tumors and their clinical outcome. Here we test the hypothesis that metabolic features determine radiosensitivity, explaining the relationship between metabolism and clinical outcome. Radiosensitivity of 14 human HNSCC cell lines was determined using colony forming assays and the expression profile of approximately 200 metabolic and cancer-related genes was generated using targeted RNA sequencing by single molecule molecular inversion probes. Results: Correlation between radiosensitivity data and expression profiles yielded 18 genes associated with radiosensitivity or radioresistance, of which adenosine triphosphate (ATP) citrate lyase (ACLY) was of particular interest. Pharmacological inhibition of ACLY caused an impairment of DNA damage repair, specifically homologous recombination, and lead to radiosensitization in HNSCC cell lines. Examination of a The Cancer Genome Atlas (TCGA) cohort of HNSCC patients revealed that high expression of ACLY was predictive for radiotherapy failure, as it was only associated with poor overall survival in patients who received radiotherapy (hazard ratio of 2.00, 95% CI: 1.12-3.55; p = 0.0184). These data were further validated in an independent cohort of HNSCC patients treated with chemoradiation. Furthermore, patients with poor locoregional control after radiotherapy have significantly higher nuclear ACLY protein levels. Together, we here show that ACLY affects DNA damage repair, and is a predictive factor for radiotherapy outcome in HNSCC.
This item appears in the following Collection(s)
- Academic publications [227425]
- Electronic publications [107141]
- Faculty of Medical Sciences [86157]
- Open Access publications [76287]
Upload full text
Use your RU credentials (u/z-number and password) to log in with SURFconext to upload a file for processing by the repository team.