Skip to main content

Advertisement

SpringerLink
Log in

LncRNA OTUD6B-AS1 overexpression promoted GPX4-mediated ferroptosis to suppress radioresistance in colorectal cancer

  • RESEARCH ARTICLE
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

Background

Radiotherapy is widely employed in colorectal cancer (CRC) treatment but is often compromised by developed radioresistance. This study explored the mechanism of long non-coding RNA ovarian tumor domain containing 6B-antisense RNA1 (lncRNA OTUD6B-AS1) in CRC radioresistance through tripartite motif 16 (TRIM16).

Methods

CRC and non-cancerous tissues were collected and radioresistant CRC cells were established, with real-time quantitative polymerase chain reaction to determine gene expression in tissues and cells. Radioresistance was evaluated by cell counting kit-8 assay and immunofluorescence (γ-H2AX) and ferroptosis was tested by Western blot assay (ACSL4/GPX4) and assay kits (Fe2+/ROS/MDA/GSH). The association between ferroptosis and lncRNA OTUD6B-AS1-inhibited radioresistance was testified using ferroptosis inhibitor. The subcellular localization of lncRNA OTUD6B-AS1 was tested by the nuclear/cytoplasmic fractionation assay, with RNA immunoprecipitation assay to validate gene interactions. Rescue experiments were conducted to analyze the role of TRIM16 in CRC radioresistance.

Results

LncRNA OTUD6B-AS1 and TRIM16 were poorly expressed (P < 0.01) in CRC tissues and cells and further decreased (P < 0.01) in radioresistant CRC cells. OTUD6B-AS1 overexpression decreased cell survival (P < 0.01), increased γ-H2AX levels (P < 0.01), and elevated ferroptosis and oxidative stress (P < 0.01) after X-ray radiation. Ferroptosis inhibitor attenuated radioresistance (P < 0.01) caused by lncRNA OTUD6B-AS1 overexpression. LncRNA OTUD6B-AS1 stabilized TRIM16 mRNA via binding to HuR. TRIM16 knockdown reduced ferroptosis and increased radioresistance (P < 0.05).

Conclusion

OTUD6B-AS1 overexpression stabilized TRIM16 via binding to HuR and increased GPX4-mediated ferroptosis, thus attenuating CRC radioresistance. Our study provided a new rationale for the treatment of CRC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Baidoun F, Elshiwy K, Elkeraie Y, Merjaneh Z, Khoudari G, Sarmini MT, et al. Colorectal cancer epidemiology: recent trends and impact on outcomes. Curr Drug Targets. 2021;22(9):998–1009.

    Article  CAS  PubMed  Google Scholar 

  2. Biller LH, Schrag D. Diagnosis and treatment of metastatic colorectal cancer: a review. JAMA. 2021;325(7):669–85.

    Article  CAS  PubMed  Google Scholar 

  3. Dariya B, Aliya S, Merchant N, Alam A, Nagaraju GP. Colorectal Cancer Biology, Diagnosis, and Therapeutic Approaches. Crit Rev Oncog. 2020;25(2):71–94.

    Article  PubMed  Google Scholar 

  4. Olivares-Urbano MA, Grinan-Lison C, Marchal JA, Nunez MI. CSC radioresistance: a therapeutic challenge to improve radiotherapy effectiveness in cancer. Cells. 2020;9(7):1651.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Lei G, Zhuang L, Gan B. Targeting ferroptosis as a vulnerability in cancer. Nat Rev Cancer. 2022;22(7):381–96.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Su Y, Zhao B, Zhou L, Zhang Z, Shen Y, Lv H, et al. Ferroptosis, a novel pharmacological mechanism of anti-cancer drugs. Cancer Lett. 2020;483:127–36.

    Article  CAS  PubMed  Google Scholar 

  7. Yuan H, Li X, Zhang X, Kang R, Tang D. Identification of ACSL4 as a biomarker and contributor of ferroptosis. Biochem Biophys Res Commun. 2016;478(3):1338–43.

    Article  CAS  PubMed  Google Scholar 

  8. Lei G, Zhang Y, Koppula P, Liu X, Zhang J, Lin SH, et al. The role of ferroptosis in ionizing radiation-induced cell death and tumor suppression. Cell Res. 2020;30(2):146–62.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Bao G, Xu R, Wang X, Ji J, Wang L, Li W, et al. Identification of lncRNA signature associated with pan-cancer prognosis. IEEE J Biomed Health Inform. 2021;25(6):2317–28.

    Article  PubMed  Google Scholar 

  10. Zhang W, Fang D, Li S, Bao X, Jiang L, Sun X. Construction and validation of a novel ferroptosis-related lncrna signature to predict prognosis in colorectal cancer patients. Front Genet. 2021;12:709329.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Cai Y, Li Y, Shi C, Zhang Z, Xu J, Sun B. LncRNA OTUD6B-AS1 inhibits many cellular processes in colorectal cancer by sponging miR-21-5p and regulating PNRC2. Hum Exp Toxicol. 2021;40(9):1463–73.

    Article  CAS  PubMed  Google Scholar 

  12. Xu Z, Jiang S, Ma J, Tang D, Yan C, Fang K. Comprehensive analysis of ferroptosis-related LncRNAs in breast cancer patients reveals prognostic value and relationship with tumor immune microenvironment. Front Surg. 2021;8:742360.

    Article  PubMed Central  PubMed  Google Scholar 

  13. Yoon JH, Abdelmohsen K, Gorospe M. Posttranscriptional gene regulation by long noncoding RNA. J Mol Biol. 2013;425(19):3723–30.

    Article  CAS  PubMed  Google Scholar 

  14. Mandell MA, Saha B, Thompson TA. The tripartite nexus: autophagy, cancer, and tripartite motif-containing protein family members. Front Pharmacol. 2020;11:308.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Ruan L, Liu W, Yang Y, Chu Z, Yang C, Yang T, et al. TRIM16 overexpression inhibits the metastasis of colorectal cancer through mediating Snail degradation. Exp Cell Res. 2021;406(1): 112735.

    Article  CAS  PubMed  Google Scholar 

  16. Li JH, Liu S, Zhou H, Qu LH, Yang JH. starBase v2.0: decoding miRNA-ceRNA, miRNA-ncRNA and protein-RNA interaction networks from large-scale CLIP-Seq data. Nucleic Acids Res. 2014;42(Database issue):D92-7.

    Article  CAS  PubMed  Google Scholar 

  17. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25(4):402–8.

    Article  CAS  PubMed  Google Scholar 

  18. Wang W, Cheng X, Zhu J. Long non-coding RNA OTUD6B-AS1 overexpression inhibits the proliferation, invasion and migration of colorectal cancer cells via downregulation of microRNA-3171. Oncol Lett. 2021;21(3):193.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Tang X, Ding H, Liang M, Chen X, Yan Y, Wan N, et al. Curcumin induces ferroptosis in non-small-cell lung cancer via activating autophagy. Thorac Cancer. 2021;12(8):1219–30.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Priyanka P, Sharma M, Das S, Saxena S. The lncRNA HMS recruits RNA-binding protein HuR to stabilize the 3’-UTR of HOXC10 mRNA. J Biol Chem. 2021;297(2): 100997.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Lei G, Mao C, Yan Y, Zhuang L, Gan B. Ferroptosis, radiotherapy, and combination therapeutic strategies. Protein Cell. 2021;12(11):836–57.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Ye LF, Chaudhary KR, Zandkarimi F, Harken AD, Kinslow CJ, Upadhyayula PS, et al. Radiation-induced lipid peroxidation triggers ferroptosis and synergizes with ferroptosis inducers. ACS Chem Biol. 2020;15(2):469–84.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Ghafouri-Fard S, Hussen BM, Gharebaghi A, Eghtedarian R, Taheri M. LncRNA signature in colorectal cancer. Pathol Res Pract. 2021;222:153432.

    Article  CAS  PubMed  Google Scholar 

  24. Wang Y, Lu JH, Wu QN, Jin Y, Wang DS, Chen YX, et al. LncRNA LINRIS stabilizes IGF2BP2 and promotes the aerobic glycolysis in colorectal cancer. Mol Cancer. 2019;18(1):174.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Tang J, Yan T, Bao Y, Shen C, Yu C, Zhu X, et al. LncRNA GLCC1 promotes colorectal carcinogenesis and glucose metabolism by stabilizing c-Myc. Nat Commun. 2019;10(1):3499.

    Article  PubMed Central  PubMed  Google Scholar 

  26. Zhou L, Jiang J, Huang Z, Jin P, Peng L, Luo M, et al. Hypoxia-induced lncRNA STEAP3-AS1 activates Wnt/beta-catenin signaling to promote colorectal cancer progression by preventing m(6)A-mediated degradation of STEAP3 mRNA. Mol Cancer. 2022;21(1):168.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Zhang M, Weng W, Zhang Q, Wu Y, Ni S, Tan C, et al. The lncRNA NEAT1 activates Wnt/beta-catenin signaling and promotes colorectal cancer progression via interacting with DDX5. J Hematol Oncol. 2018;11(1):113.

    Article  PubMed Central  PubMed  Google Scholar 

  28. Wang L, Cho KB, Li Y, Tao G, Xie Z, Guo B. Long noncoding RNA (lncRNA)-mediated competing endogenous RNA networks provide novel potential biomarkers and therapeutic targets for colorectal cancer. Int J Mol Sci. 2019;20(22):5758.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Wang Z, Xia F, Feng T, Jiang B, Wang W, Li X. OTUD6B-AS1 Inhibits Viability, Migration, and Invasion of Thyroid Carcinoma by Targeting miR-183–5p and miR-21. Front Endocrinol (Lausanne). 2020. https://doi.org/10.3389/fendo.2020.00136.

    Article  PubMed Central  PubMed  Google Scholar 

  30. Wang G, Zhang ZJ, Jian WG, Liu PH, Xue W, Wang TD, et al. Novel long noncoding RNA OTUD6B-AS1 indicates poor prognosis and inhibits clear cell renal cell carcinoma proliferation via the Wnt/beta-catenin signaling pathway. Mol Cancer. 2019;18(1):15.

    Article  PubMed Central  PubMed  Google Scholar 

  31. Li PP, Li RG, Huang YQ, Lu JP, Zhang WJ, Wang ZY. LncRNA OTUD6B-AS1 promotes paclitaxel resistance in triple negative breast cancer by regulation of miR-26a-5p/MTDH pathway-mediated autophagy and genomic instability. Aging (Albany NY). 2021;13(21):24171–91.

    Article  CAS  PubMed  Google Scholar 

  32. Kong S, Xue H, Li Y, Li P, Ma F, Liu M, et al. The long noncoding RNA OTUD6B-AS1 enhances cell proliferation and the invasion of hepatocellular carcinoma cells through modulating GSKIP/Wnt/beta-catenin signalling via the sequestration of miR-664b-3p. Exp Cell Res. 2020;395(1): 112180.

    Article  CAS  PubMed  Google Scholar 

  33. Hou H, Yu R, Zhao H, Yang H, Hu Y, Hu Y, et al. LncRNA OTUD6B-as1 induces cisplatin resistance in cervical cancer cells through up-regulating cyclin D2 via miR-206. Front Oncol. 2021;11: 777220.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Santivasi WL, Xia F. Ionizing radiation-induced DNA damage, response, and repair. Antioxid Redox Signal. 2014;21(2):251–9.

    Article  CAS  PubMed  Google Scholar 

  35. Sharma A, Singh K, Almasan A. Histone H2AX phosphorylation: a marker for DNA damage. Methods Mol Biol. 2012;920:613–26.

    Article  CAS  PubMed  Google Scholar 

  36. Wang Y, Yang T, Han Y, Ren Z, Zou J, Liu J, et al. lncRNA OTUD6B-AS1 exacerbates As(2)O(3)-induced oxidative damage in bladder cancer via miR-6734–5p-mediated functional inhibition of IDH2. Oxid Med Cell Longev. 2020. https://doi.org/10.1155/2020/3035624.

    Article  PubMed Central  PubMed  Google Scholar 

  37. Peng WX, Koirala P, Zhang W, Ni C, Wang Z, Yang L, et al. lncRNA RMST enhances DNMT3 expression through Interaction with HuR. Mol Ther. 2020;28(1):9–18.

    Article  CAS  PubMed  Google Scholar 

  38. Tian H, Lian R, Li Y, Liu C, Liang S, Li W, et al. AKT-induced lncRNA VAL promotes EMT-independent metastasis through diminishing Trim16-dependent Vimentin degradation. Nat Commun. 2020;11(1):5127.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Roshanazadeh MR, Adelipour M, Sanaei A, Chenane H, Rashidi M. TRIM3 and TRIM16 as potential tumor suppressors in breast cancer patients. BMC Res Notes. 2022;15(1):312.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Nagy Z, Cheung BB, Tsang W, Tan O, Herath M, Ciampa OC, et al. Withaferin A activates TRIM16 for its anti-cancer activity in melanoma. Sci Rep. 2020;10(1):19724.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Li Q, Chen K, Dong R, Lu H. LncRNA CASC2 inhibits autophagy and promotes apoptosis in non-small cell lung cancer cells via regulating the miR-214/TRIM16 axis. RSC Adv. 2018;8(71):40846–55.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Xie T, Tan M, Gao Y, Yang H. CRABP2 accelerates epithelial mesenchymal transition in serous ovarian cancer cells by promoting TRIM16 methylation via upregulating EZH2 expression. Environ Toxicol. 2022;37(8):1957–67.

    Article  CAS  PubMed  Google Scholar 

  43. Huo X, Li S, Shi T, Suo A, Ruan Z, Yao Y. Tripartite motif 16 inhibits epithelial-mesenchymal transition and metastasis by down-regulating sonic hedgehog pathway in non-small cell lung cancer cells. Biochem Biophys Res Commun. 2015;460(4):1021–8.

    Article  CAS  PubMed  Google Scholar 

  44. Wang Y, Wu Y, Xie S. CircPTK2 inhibits cell cisplatin (CDDP) resistance by targeting miR-942/TRIM16 axis in non-small cell lung cancer (NSCLC). Bioengineered. 2022;13(2):3651–64.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Wang N, Zhang T. Downregulation of microRNA-135 promotes sensitivity of non-small cell lung cancer to gefitinib by targeting TRIM16. Oncol Res. 2018;26(7):1005–14.

    Article  PubMed Central  PubMed  Google Scholar 

  46. Sutton SK, Carter DR, Kim P, Tan O, Arndt GM, Zhang XD, et al. A novel compound which sensitizes BRAF wild-type melanoma cells to vemurafenib in a TRIM16-dependent manner. Oncotarget. 2016;7(32):52166–78.

    Article  PubMed Central  PubMed  Google Scholar 

  47. Yao J, Xu T, Tian T, Fu X, Wang W, Li S, et al. Tripartite motif 16 suppresses breast cancer stem cell properties through regulation of Gli-1 degradation via the ubiquitin-proteasome pathway. Oncol Rep. 2016;35(2):1204–12.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by the Special Fund of Foshan Summit Plan (No. 2019C020) and the Construction Funds for High-level Medical Key Specialty Projects in Foshan during the 14th Five Year Plan Period (No. 0660215).

Author information

Authors and Affiliations

  1. Department of General Surgery, Jinling Hospital, the First School of Clinical Medicine, Southern Medical University, 305 Zhongshan East Road, Nanjing, 210002, Jiangsu, China

    Zilang Zhang, Baolong Ye & Wu Ji

  2. Department of Anorectal Surgery, The First People’s Hospital of Foshan, 81 Lingnan Avenue North, Foshan, 528000, Guangdong, China

    Zilang Zhang, Yiban Lin & Jianzhong Deng

  3. Department of General Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China

    Wenjun Liu

Authors
  1. Zilang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Baolong Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yiban Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wenjun Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jianzhong Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wu Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: ZZ, BY, YL; Formal analysis and investigation: ZZ, WL; Writing—original draft preparation: ZZ, WL, JD; Writing—review and editing: ZZ, WJ. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Jianzhong Deng or Wu Ji.

Ethics declarations

Conflict of interest

The authors have declared no conflicts of interest.

Ethical approval

This study conformed to the Declaration of Helsinki and got the approval of the Ethics Committee of Jinling Hospital, the First School of Clinical Medicine, Southern Medical University.

Informed consent

Each patient signed the written informed consent.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, Z., Ye, B., Lin, Y. et al. LncRNA OTUD6B-AS1 overexpression promoted GPX4-mediated ferroptosis to suppress radioresistance in colorectal cancer. Clin Transl Oncol 25, 3217–3229 (2023). https://doi.org/10.1007/s12094-023-03193-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-023-03193-7

Keywords

Search

Navigation