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<p>Non-coding RNAs (ncRNAs) have important regulatory functions similar to traditional oncogenes or tumor suppressor genes. Our previous research found a novel pan-cancer downexpressed ncRNA, <i>PANC754</i>. However, its function and underlying mechanism remain obscure in colorectal cancer (CRC). In this study, in vitro and in vivo experiments were performed to determine the function of <i>PANC754</i>. Loss and gain of function experiments, molecular docking experiments, and bioinformatic analysis were utilized to visualize its pathway. Co-culture system was leveraged to explore its effect on synergetic immune checkpoint blockage against CRC. Through a series of studies, we found that overexpressed <i>PANC754</i> significantly inhibited cell viability, migration, and metastasis and induced notable apoptosis in CRC. The mechanical research found that PANC754 was the nuclear-located and its expression was regulated by m<sup>6</sup>A modification via METTL3 enzyme, which bound with its RBP PSPC1, then interacted with H3K4me1 to chromatin-accessible inhibit immune evasive molecule LGALS7 and led to suppress CRC progress. Furthermore, we confirmed that prominent upregulation of the immune checkpoint inhibitory (ICI) capability of anti-NKG2A, monalizumab when it was combined with PANC754 overexpression. Collectively, our study revealed that <i>PANC754</i> is a tumor-suppressing ncRNA to form an ncRNA/RBP/histone repression complex with m<sup>6</sup>A-dependence, which can enhance the immune therapeutics effect of ICI, suggesting a promising therapeutic target.</p><p></p>

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M6A-METTL3-dependent nuclear PANC754/PSPC1/H3K4me1 repression complex regulate immune evasive LGALS7 signal to enhance immunotherapy against colorectal cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月9日

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  • Jianfeng Zhang,
  • Guilian Cao,
  • Feng Li,
  • Siyu Tang,
  • Chenxi Wu,
  • Min Jiang,
  • Jingxin Ye,
  • Shaoqing Ju,
  • Fei Qian,
  • Weifeng Ding

摘要

Non-coding RNAs (ncRNAs) have important regulatory functions similar to traditional oncogenes or tumor suppressor genes. Our previous research found a novel pan-cancer downexpressed ncRNA, PANC754. However, its function and underlying mechanism remain obscure in colorectal cancer (CRC). In this study, in vitro and in vivo experiments were performed to determine the function of PANC754. Loss and gain of function experiments, molecular docking experiments, and bioinformatic analysis were utilized to visualize its pathway. Co-culture system was leveraged to explore its effect on synergetic immune checkpoint blockage against CRC. Through a series of studies, we found that overexpressed PANC754 significantly inhibited cell viability, migration, and metastasis and induced notable apoptosis in CRC. The mechanical research found that PANC754 was the nuclear-located and its expression was regulated by m6A modification via METTL3 enzyme, which bound with its RBP PSPC1, then interacted with H3K4me1 to chromatin-accessible inhibit immune evasive molecule LGALS7 and led to suppress CRC progress. Furthermore, we confirmed that prominent upregulation of the immune checkpoint inhibitory (ICI) capability of anti-NKG2A, monalizumab when it was combined with PANC754 overexpression. Collectively, our study revealed that PANC754 is a tumor-suppressing ncRNA to form an ncRNA/RBP/histone repression complex with m6A-dependence, which can enhance the immune therapeutics effect of ICI, suggesting a promising therapeutic target.