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

• Zilang Zhang ^[1] ; Baolong Ye ^[1] ; Yiban Lin ^[3] ; Wenjun Liu ^[2] ; Jianzhong Deng ^[3] ; Wu Ji ^[1]
  1. [1] Southern Medical University

     Southern Medical University

     China

     
  2. [2] Third Affiliated Hospital of Guangzhou Medical University

     Third Affiliated Hospital of Guangzhou Medical University

     China

     
  3. [3] Department of Anorectal Surgery, The First People’s Hospital of Foshan, 81 Lingnan Avenue North, Foshan, 528000, Guangdong, China

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• Localización: Clinical & translational oncology, ISSN 1699-048X, Vol. 25, Nº. 11 (November), 2023, págs. 3217-3229
• Idioma: inglés
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• Resumen

  • 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.