CYLD: A Key Factor and Novel Predictive Biomarker of Cross-Resistance to Chemotherapy and Radiotherapy in Oral Squamous Cell Carcinoma.
7 affiliations
- 1Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
- 2Institute for Advanced Biosciences, Keio University, 403-1 Nihonkoku, Daiboji, Tsuruoka-shi, Yamagata 997-0017, Japan.
- 3Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto, 860-0811 Japan.
- 4Department of Oral & Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-Ku, Kumamoto, 860-8556 Japan.
- 5Division of Radiation Biology and Medicine, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, 1-15-1, Fukumuro, Miyagino, Sendai, Miyagi, Japan.
- 6Department of Pharmacy, Kumamoto University Hospital, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
- 7Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA.
Abstract
Cross-resistance to chemotherapy and radiotherapy is a major obstacle in cancer treatment and strongly associated with poor prognosis. Particularly, oral squamous cell carcinoma (OSCC) frequently exhibits such cross-resistance, limiting the efficacy of standard chemoradiotherapy. To unveil its molecular mechanism, we took advantage of a comprehensive proteomic analysis using clinically relevant radio-resistant OSCC cells, and identified distinct alterations in protein expression. Among the differentially expressed proteins, we focused on the down-regulation of cylindromatosis (CYLD), a deubiquitinating enzyme and tumor suppressor. Suppression of CYLD expression in OSCC cells led to accumulation of DNA damage and increased cross-resistance. CYLD down-regulation caused cross-resistance in OSCC cells, at least in part, via NF-κB hyperactivation. Notably, EGFR-TKI monotherapy demonstrated significant efficacy against cross-resistant OSCC in vitro and in vivo. Moreover, in patient-derived xenograft (PDX) models, CYLD expression might serve as a potential predictive biomarker for EGFR-TKI responsiveness in cross-resistant OSCC. These findings highlight the pivotal role of CYLD down-regulation driving OSCC progression via cross-resistance and offer new prospects for the clinical application of EGFR-TKIs, with CYLD expression serving as a potential predictive biomarker for OSCC patient with cross-resistance.
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BibTeX
@article{yonemaru2026cyld,
title = {{CYLD: A Key Factor and Novel Predictive Biomarker of Cross-Resistance to Chemotherapy and Radiotherapy in Oral Squamous Cell Carcinoma.}},
author = {Kou Yonemaru and Naoki Suenaga and Takeshi Masuda and Ryusho Kariya and Yuki Seki and Ryoji Yoshida and Hideki Nakayama and Yoshikazu Kuwahara and Fumihiro Nishimura and Kazutaka Oda and Jian-Dong Li and Hirofumi Jono},
journal = {International journal of biological sciences},
year = {2026},
month = oct,
doi = {10.7150/ijbs.138201},
url = {https://europepmc.org/article/MED/42910291},
note = {CC BY},
}
RIS
TY - JOUR
TI - CYLD: A Key Factor and Novel Predictive Biomarker of Cross-Resistance to Chemotherapy and Radiotherapy in Oral Squamous Cell Carcinoma.
AU - Kou Yonemaru
AU - Naoki Suenaga
AU - Takeshi Masuda
AU - Ryusho Kariya
AU - Yuki Seki
AU - Ryoji Yoshida
AU - Hideki Nakayama
AU - Yoshikazu Kuwahara
AU - Fumihiro Nishimura
AU - Kazutaka Oda
AU - Jian-Dong Li
AU - Hirofumi Jono
PY - 2026
DA - 2026/10/02
JO - International journal of biological sciences
DO - 10.7150/ijbs.138201
UR - https://europepmc.org/article/MED/42910291
AB - Cross-resistance to chemotherapy and radiotherapy is a major obstacle in cancer treatment and strongly associated with poor prognosis. Particularly, oral squamous cell carcinoma (OSCC) frequently exhibits such cross-resistance, limiting the efficacy of standard chemoradiotherapy. To unveil its molecular mechanism, we took advantage of a comprehensive proteomic analysis using clinically relevant radio-resistant OSCC cells, and identified distinct alterations in protein expression. Among the differentially expressed proteins, we focused on the down-regulation of cylindromatosis (CYLD), a deubiquitinating enzyme and tumor suppressor. Suppression of CYLD expression in OSCC cells led to accumulation of DNA damage and increased cross-resistance. CYLD down-regulation caused cross-resistance in OSCC cells, at least in part, via NF-κB hyperactivation. Notably, EGFR-TKI monotherapy demonstrated significant efficacy against cross-resistant OSCC in vitro and in vivo. Moreover, in patient-derived xenograft (PDX) models, CYLD expression might serve as a potential predictive biomarker for EGFR-TKI responsiveness in cross-resistant OSCC. These findings highlight the pivotal role of CYLD down-regulation driving OSCC progression via cross-resistance and offer new prospects for the clinical application of EGFR-TKIs, with CYLD expression serving as a potential predictive biomarker for OSCC patient with cross-resistance.
SN - 1449-2288
ER -