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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2024

Open Access 01-12-2024 | Radiotherapy | Research

CircCDYL2 bolsters radiotherapy resistance in nasopharyngeal carcinoma by promoting RAD51 translation initiation for enhanced homologous recombination repair

Authors: Hongke Qu, Yumin Wang, Qijia Yan, Chunmei Fan, Xiangyan Zhang, Dan Wang, Can Guo, Pan Chen, Lei Shi, Qianjin Liao, Ming Zhou, Fuyan Wang, Zhaoyang Zeng, Bo Xiang, Wei Xiong

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2024

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Abstract

Background

Radiation therapy stands to be one of the primary approaches in the clinical treatment of malignant tumors. Nasopharyngeal Carcinoma, a malignancy predominantly treated with radiation therapy, provides an invaluable model for investigating the mechanisms underlying radiation therapy resistance in cancer. While some reports have suggested the involvement of circRNAs in modulating resistance to radiation therapy, the underpinning mechanisms remain unclear.

Methods

RT-qPCR and in situ hybridization were used to detect the expression level of circCDYL2 in nasopharyngeal carcinoma tissue samples. The effect of circCDYL2 on radiotherapy resistance in nasopharyngeal carcinoma was demonstrated by in vitro and in vivo functional experiments. The HR-GFP reporter assay determined that circCDYL2 affected homologous recombination repair. RNA pull down, RIP, western blotting, IF, and polysome profiling assays were used to verify that circCDYL2 promoted the translation of RAD51 by binding to EIF3D protein.

Results

We have identified circCDYL2 as highly expressed in nasopharyngeal carcinoma tissues, and it was closely associated with poor prognosis. In vitro and in vivo experiments demonstrate that circCDYL2 plays a pivotal role in promoting radiotherapy resistance in nasopharyngeal carcinoma. Our investigation unveils a specific mechanism by which circCDYL2, acting as a scaffold molecule, recruits eukaryotic translation initiation factor 3 subunit D protein (EIF3D) to the 5′-UTR of RAD51 mRNA, a crucial component of the DNA damage repair pathway to facilitate the initiation of RAD51 translation and enhance homologous recombination repair capability, and ultimately leads to radiotherapy resistance in nasopharyngeal carcinoma.

Conclusions

These findings establish a novel role of the circCDYL2/EIF3D/RAD51 axis in nasopharyngeal carcinoma radiotherapy resistance. Our work not only sheds light on the underlying molecular mechanism but also highlights the potential of circCDYL2 as a therapeutic sensitization target and a promising prognostic molecular marker for nasopharyngeal carcinoma.
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Literature
1.
2.
Chang ET, Adami HO. The enigmatic epidemiology of nasopharyngeal carcinoma. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2006;15(10):1765–77.CrossRef
3.
Chen Y, Zhao Y, Yang X, Ren X, Huang S, Gong S, et al. USP44 regulates irradiation-induced DNA double-strand break repair and suppresses tumorigenesis in nasopharyngeal carcinoma. Nat Commun. 2022;13(1):501.PubMedPubMedCentralCrossRef
4.
Wei F, Wu Y, Tang L, He Y, Shi L, Xiong F, et al. BPIFB1 (LPLUNC1) inhibits migration and invasion of nasopharyngeal carcinoma by interacting with VTN and VIM. Br J Cancer. 2018;118(2):233–47.PubMedCrossRef
5.
Wang WJ, Wu SP, Liu JB, Shi YS, Huang X, Zhang QB, et al. MYC regulation of CHK1 and CHK2 promotes radioresistance in a stem cell-like population of nasopharyngeal carcinoma cells. Cancer Res. 2013;73(3):1219–31.PubMedCrossRef
6.
Hassan KA, Ang KK, El-Naggar AK, Story MD, Lee JI, Liu D, et al. Cyclin B1 overexpression and resistance to radiotherapy in head and neck squamous cell carcinoma. Cancer Res. 2002;62(22):6414–7.PubMed
7.
Feng XP, Yi H, Li MY, Li XH, Yi B, Zhang PF, et al. Identification of biomarkers for predicting nasopharyngeal carcinoma response to radiotherapy by proteomics. Cancer Res. 2010;70(9):3450–62.PubMedCrossRef
8.
Batenburg NL, Walker JR, Noordermeer SM, Moatti N, Durocher D, Zhu XD. ATM and CDK2 control chromatin remodeler CSB to inhibit RIF1 in DSB repair pathway choice. Nat Commun. 2017;8(1):1921.PubMedPubMedCentralCrossRef
9.
Lee KJ, Saha J, Sun J, Fattah KR, Wang SC, Jakob B, et al. Phosphorylation of Ku dictates DNA double-strand break (DSB) repair pathway choice in S phase. Nucleic Acids Res. 2016;44(4):1732–45.PubMedCrossRef
10.
Kang YJ, Yan CT. Regulation of DNA repair in the absence of classical non-homologous end joining. DNA repair. 2018;68:34–40.PubMedCrossRef
11.
Ceccaldi R, Rondinelli B, D'Andrea AD. Repair pathway choices and consequences at the double-Strand break. Trends Cell Biol. 2016;26(1):52–64.PubMedCrossRef
12.
Li X, Heyer WD. Homologous recombination in DNA repair and DNA damage tolerance. Cell Res. 2008;18(1):99–113.PubMedCrossRef
13.
Laurini E, Marson D, Fermeglia A, Aulic S, Fermeglia M, Pricl S. Role of Rad51 and DNA repair in cancer: a molecular perspective. Pharmacol Ther. 2020;208:107492.PubMedCrossRef
14.
Orhan E, Velazquez C, Tabet I, Sardet C, Theillet C. Regulation of RAD51 at the transcriptional and functional levels: what prospects for Cancer therapy? Cancers. 2021;13(12):2930.PubMedPubMedCentralCrossRef
15.
Biehs R, Steinlage M, Barton O, Juhász S, Künzel J, Spies J, et al. DNA double-Strand break resection occurs during non-homologous end joining in G1 but is distinct from resection during homologous recombination. Mol Cell. 2017;65(4):671–84.e5.PubMedPubMedCentralCrossRef
16.
Mo Y, Wang Y, Wang Y, Deng X, Yan Q, Fan C, et al. Circular RNA circPVT1 promotes nasopharyngeal carcinoma metastasis via the beta-TrCP/c-Myc/SRSF1 positive feedback loop. Mol Cancer. 2022;21(1):192.PubMedPubMedCentralCrossRef
17.
Mo Y, Wang Y, Zhang S, Xiong F, Yan Q, Jiang X, et al. Circular RNA circRNF13 inhibits proliferation and metastasis of nasopharyngeal carcinoma via SUMO2. Mol Cancer. 2021;20(1):112.PubMedPubMedCentralCrossRef
18.
Ge J, Wang J, Xiong F, Jiang X, Zhu K, Wang Y, et al. Epstein-Barr virus-encoded circular RNA CircBART2.2 promotes immune escape of nasopharyngeal carcinoma by regulating PD-L1. Cancer Res. 2021;81(19):5074–88.PubMedPubMedCentralCrossRef
19.
Wang Y, Yan Q, Mo Y, Liu Y, Wang Y, Zhang S, et al. Splicing factor derived circular RNA circCAMSAP1 accelerates nasopharyngeal carcinoma tumorigenesis via a SERPINH1/c-Myc positive feedback loop. Mol Cancer. 2022;21(1):62.PubMedPubMedCentralCrossRef
20.
Wu P, Hou X, Peng M, Deng X, Yan Q, Fan C, et al. Circular RNA circRILPL1 promotes nasopharyngeal carcinoma malignant progression by activating the hippo-YAP signaling pathway. Cell Death Differ. 2023;30(7):1679–94.PubMedCrossRef
21.
Tang L, Xiong W, Zhang L, Wang D, Wang Y, Wu Y, et al. circSETD3 regulates MAPRE1 through miR-615-5p and miR-1538 sponges to promote migration and invasion in nasopharyngeal carcinoma. Oncogene. 2021;40(2):307–21.PubMedCrossRef
22.
Fan C, Qu H, Xiong F, Tang Y, Tang T, Zhang L, et al. CircARHGAP12 promotes nasopharyngeal carcinoma migration and invasion via ezrin-mediated cytoskeletal remodeling. Cancer Lett. 2021;496:41–56.PubMedCrossRef
23.
Yang M, Huang W. Circular RNAs in nasopharyngeal carcinoma. Clinica chimica acta; international journal of clinical chemistry. 2020;508:240–8.PubMedCrossRef
24.
Cui C, Yang J, Li X, Liu D, Fu L, Wang X. Functions and mechanisms of circular RNAs in cancer radiotherapy and chemotherapy resistance. Mol Cancer. 2020;19(1):58.PubMedPubMedCentralCrossRef
25.
Zhao J, Tian S, Guo Q, Bao K, Yu G, Wang X, et al. A PARylation-phosphorylation cascade promotes TOPBP1 loading and RPA-RAD51 exchange in homologous recombination. Mol Cell. 2022;82(14):2571–87 e9.PubMedCrossRef
26.
Li JY, Zhao Y, Gong S, Wang MM, Liu X, He QM, et al. TRIM21 inhibits irradiation-induced mitochondrial DNA release and impairs antitumour immunity in nasopharyngeal carcinoma tumour models. Nat Commun. 2023;14(1):865.PubMedPubMedCentralCrossRef
27.
Lu J, Tang M, Li H, Xu Z, Weng X, Li J, et al. EBV-LMP1 suppresses the DNA damage response through DNA-PK/AMPK signaling to promote radioresistance in nasopharyngeal carcinoma. Cancer Lett. 2016;380(1):191–200.PubMedCrossRef
28.
Choudhury A, Zhao H, Jalali F, Al Rashid S, Ran J, Supiot S, et al. Targeting homologous recombination using imatinib results in enhanced tumor cell chemosensitivity and radiosensitivity. Mol Cancer Ther. 2009;8(1):203–13.PubMedCrossRef
29.
Walker JR, Corpina RA, Goldberg J. Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair. Nature. 2001;412(6847):607–14.PubMedCrossRef
30.
Mao Z, Hine C, Tian X, Van Meter M, Au M, Vaidya A, et al. SIRT6 promotes DNA repair under stress by activating PARP1. Science (New York, NY). 2011;332(6036):1443–6.CrossRef
31.
Pierce AJ, Hu P, Han M, Ellis N, Jasin M. Ku DNA end-binding protein modulates homologous repair of double-strand breaks in mammalian cells. Genes Dev. 2001;15(24):3237–42.PubMedPubMedCentralCrossRef
32.
Yu H, Bu C, Liu Y, Gong T, Liu X, Liu S, et al. Global crotonylome reveals CDYL-regulated RPA1 crotonylation in homologous recombination-mediated DNA repair. Sci Adv. 2020;6(11):eaay4697.PubMedPubMedCentralCrossRef
33.
Huang R, Zhou PK. DNA damage repair: historical perspectives, mechanistic pathways and clinical translation for targeted cancer therapy. Signal transduction and targeted therapy. 2021;6(1):254.PubMedPubMedCentralCrossRef
34.
Hussmann JA, Ling J, Ravisankar P, Yan J, Cirincione A, Xu A, et al. Mapping the genetic landscape of DNA double-strand break repair. Cell. 2021;184(22):5653–69.e25.PubMedPubMedCentralCrossRef
35.
He Y, Jing Y, Wei F, Tang Y, Yang L, Luo J, et al. Long non-coding RNA PVT1 predicts poor prognosis and induces radioresistance by regulating DNA repair and cell apoptosis in nasopharyngeal carcinoma. Cell Death Dis. 2018;9(2):235.PubMedPubMedCentralCrossRef
36.
Arnould C, Rocher V, Finoux AL, Clouaire T, Li K, Zhou F, et al. Loop extrusion as a mechanism for formation of DNA damage repair foci. Nature. 2021;590(7847):660–5.PubMedPubMedCentralCrossRef
37.
Xie Y, Liu YK, Guo ZP, Guan H, Liu XD, Xie DF, et al. RBX1 prompts degradation of EXO1 to limit the homologous recombination pathway of DNA double-strand break repair in G1 phase. Cell Death Differ. 2020;27(4):1383–97.PubMedCrossRef
38.
Sizemore ST, Zhang M, Cho JH, Sizemore GM, Hurwitz B, Kaur B, et al. Pyruvate kinase M2 regulates homologous recombination-mediated DNA double-strand break repair. Cell Res. 2018;28(11):1090–102.PubMedPubMedCentralCrossRef
39.
Foo TK, Xia B. BRCA1-dependent and independent recruitment of PALB2-BRCA2-RAD51 in the DNA damage response and Cancer. Cancer Res. 2022;82(18):3191–7.PubMedCrossRef
40.
Guo Z, Wang YH, Xu H, Yuan CS, Zhou HH, Huang WH, et al. LncRNA linc00312 suppresses radiotherapy resistance by targeting DNA-PKcs and impairing DNA damage repair in nasopharyngeal carcinoma. Cell Death Dis. 2021;12(1):69.PubMedPubMedCentralCrossRef
41.
Wang D, Zhou Z, Wu E, Ouyang C, Wei G, Wang Y, et al. LRIK interacts with the Ku70-Ku80 heterodimer enhancing the efficiency of NHEJ repair. Cell Death Differ. 2020;27(12):3337–53.PubMedPubMedCentralCrossRef
42.
Cheng Z, Yu C, Cui S, Wang H, Jin H, Wang C, et al. circTP63 functions as a ceRNA to promote lung squamous cell carcinoma progression by upregulating FOXM1. Nat Commun. 2019;10(1):3200.PubMedPubMedCentralCrossRef
43.
Li B, Zhu L, Lu C, Wang C, Wang H, Jin H, et al. circNDUFB2 inhibits non-small cell lung cancer progression via destabilizing IGF2BPs and activating anti-tumor immunity. Nat Commun. 2021;12(1):295.PubMedPubMedCentralCrossRef
44.
Chen LL. The biogenesis and emerging roles of circular RNAs. Nat Rev Mol Cell Biol. 2016;17(4):205–11.PubMedCrossRef
45.
Ashwal-Fluss R, Meyer M, Pamudurti NR, Ivanov A, Bartok O, Hanan M, et al. circRNA biogenesis competes with pre-mRNA splicing. Mol Cell. 2014;56(1):55–66.PubMedCrossRef
46.
Lv JF, Hu L, Zhuo W, Zhang CM, Zhou HH, Fan L. Epigenetic alternations and cancer chemotherapy response. Cancer Chemother Pharmacol. 2016;77(4):673–84.PubMedCrossRef
47.
Wu P, Mo Y, Peng M, Tang T, Zhong Y, Deng X, et al. Emerging role of tumor-related functional peptides encoded by lncRNA and circRNA. Mol Cancer. 2020;19(1):22.PubMedPubMedCentralCrossRef
48.
Zhang M, Zhao K, Xu X, Yang Y, Yan S, Wei P, et al. A peptide encoded by circular form of LINC-PINT suppresses oncogenic transcriptional elongation in glioblastoma. Nat Commun. 2018;9(1):4475.PubMedPubMedCentralCrossRef
49.
Li F, Zhang Y, Shi Y, Liu S. Comprehensive analysis of prognostic and immune infiltrates for RAD51 in human breast Cancer. Crit Rev Eukaryot Gene Expr. 2021;31(4):71–9.PubMedCrossRef
50.
Deng Y, Guo W, Xu N, Li F, Li J. CtBP1 transactivates RAD51 and confers cisplatin resistance to breast cancer cells. Mol Carcinog. 2020;59(5):512–9.PubMedCrossRef
51.
Lee JO, Kang MJ, Byun WS, Kim SA, Seo IH, Han JA, et al. Metformin overcomes resistance to cisplatin in triple-negative breast cancer (TNBC) cells by targeting RAD51. Breast cancer research : BCR. 2019;21(1):115.PubMedPubMedCentralCrossRef
52.
Li X, Wang J, Long H, Lin W, Wang H, Chen Y, et al. circCDYL2, overexpressed in highly migratory colorectal Cancer cells, promotes migration by binding to Ezrin. Front Oncol. 2021;11:716073.PubMedPubMedCentralCrossRef
53.
Ling Y, Liang G, Lin Q, Fang X, Luo Q, Cen Y, et al. circCDYL2 promotes trastuzumab resistance via sustaining HER2 downstream signaling in breast cancer. Mol Cancer. 2022;21(1):8.PubMedPubMedCentralCrossRef
54.
Song P, Yang F, Jin H, Wang X. The regulation of protein translation and its implications for cancer. Signal transduction and targeted therapy. 2021;6(1):68.PubMedPubMedCentralCrossRef
55.
Rubio A, Garland GD, Sfakianos A, Harvey RF, Willis AE. Aberrant protein synthesis and cancer development: the role of canonical eukaryotic initiation, elongation and termination factors in tumorigenesis. Semin Cancer Biol. 2022;86(Pt 3):151–65.PubMedCrossRef
56.
Bjornsti MA, Houghton PJ. Lost in translation: dysregulation of cap-dependent translation and cancer. Cancer Cell. 2004;5(6):519–23.PubMedCrossRef
57.
Fabbri L, Chakraborty A, Robert C, Vagner S. The plasticity of mRNA translation during cancer progression and therapy resistance. Nat Rev Cancer. 2021;21(9):558–77.PubMedCrossRef
58.
Spilka R, Ernst C, Mehta AK, Haybaeck J. Eukaryotic translation initiation factors in cancer development and progression. Cancer Lett. 2013;340(1):9–21.PubMedCrossRef
59.
des Georges A, Dhote V, Kuhn L, Hellen CU, Pestova TV, Frank J, et al. Structure of mammalian eIF3 in the context of the 43S preinitiation complex. Nature. 2015;525(7570):491–5.PubMedPubMedCentralCrossRef
60.
Zhang W, Sun Y, Bai L, Zhi L, Yang Y, Zhao Q, et al. RBMS1 regulates lung cancer ferroptosis through translational control of SLC7A11. J Clin Invest. 2021;131(22):e152067.
Metadata
Title
CircCDYL2 bolsters radiotherapy resistance in nasopharyngeal carcinoma by promoting RAD51 translation initiation for enhanced homologous recombination repair
Authors
Hongke Qu
Yumin Wang
Qijia Yan
Chunmei Fan
Xiangyan Zhang
Dan Wang
Can Guo
Pan Chen
Lei Shi
Qianjin Liao
Ming Zhou
Fuyan Wang
Zhaoyang Zeng
Bo Xiang
Wei Xiong
Publication date
01-12-2024
Publisher
BioMed Central
Keyword
Radiotherapy
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2024
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-024-03049-0

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