Scholarlink

<p>Cancer stem cells (CSCs) are closely associated with drug resistance and recurrence in ovarian cancer patients. Although leptin is a high-risk factor for ovarian cancer and promotes stemness maintenance, a therapeutic strategy that counteracts the downstream signaling pathway of leptin remains elusive. Herein, the deubiquitinase OTUD1 was identified as a critical regulator of leptin in maintaining OCSCs properties. Mechanistically, leptin treatment significantly increased the chromatin enrichment of the transcription factor c-Jun, including the <i>OTUD1</i> gene enhancer, which was sufficient to increase the OTUD1 protein level and subsequently cause OTUD1 aggresome formation, ASK1 recruitment and JNK/c-Jun pathway activation. The resultant positive feedback loop of c-Jun and OTUD1 was required for OCSCs stemness maintenance. Notably, the disruption of the positive feedback loop by targeting c-Jun or ASK1/JNK with T-5224, selonsertib, or ibrutinib markedly inhibited the leptin-induced stemness maintenance of OCSCs and tumorigenicity. Our findings reveal a crucial mechanism for leptin-mediated stemness maintenance and indicate that targeting c-Jun or the identified positive feedback loop has translational potential for ovarian cancer patients.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

A positive feedback loop of OTUD1 and c-Jun driven by leptin expedites stemness maintenance in ovarian cancer

  • 期刊论文

  • 发表日期：

    2025年3月19日

查看全文
  • Jingtao Wang,
  • Fan Yang,
  • Yurou Chen,
  • Yuzhu Xing,
  • Juyuan Huang,
  • Jing Cao,
  • Jiaqiang Xiong,
  • Yanyan Liu,
  • Qiuyan Zhao,
  • Manwen Luo,
  • Jie Xiong,
  • Guanlan Fan,
  • Qiongying Lyu,
  • Feng Li,
  • Wei Zhang

摘要

Cancer stem cells (CSCs) are closely associated with drug resistance and recurrence in ovarian cancer patients. Although leptin is a high-risk factor for ovarian cancer and promotes stemness maintenance, a therapeutic strategy that counteracts the downstream signaling pathway of leptin remains elusive. Herein, the deubiquitinase OTUD1 was identified as a critical regulator of leptin in maintaining OCSCs properties. Mechanistically, leptin treatment significantly increased the chromatin enrichment of the transcription factor c-Jun, including the OTUD1 gene enhancer, which was sufficient to increase the OTUD1 protein level and subsequently cause OTUD1 aggresome formation, ASK1 recruitment and JNK/c-Jun pathway activation. The resultant positive feedback loop of c-Jun and OTUD1 was required for OCSCs stemness maintenance. Notably, the disruption of the positive feedback loop by targeting c-Jun or ASK1/JNK with T-5224, selonsertib, or ibrutinib markedly inhibited the leptin-induced stemness maintenance of OCSCs and tumorigenicity. Our findings reveal a crucial mechanism for leptin-mediated stemness maintenance and indicate that targeting c-Jun or the identified positive feedback loop has translational potential for ovarian cancer patients.