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M6A-METTL3-dependent nuclear PANC754/PSPC1/H3K4me1 repression complex regulate immune evasive LGALS7 signal to

Jianfeng Zhang1, Guilian Cao1,2, Feng Li3

  • 1Department of Laboratory Medicine; Department of Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, Jiangsu Province, China.

Cell Death & Disease
|July 9, 2025
PubMed

Insights

This study reveals PANC754, a novel non-coding RNA, suppresses colorectal cancer (CRC) by inhibiting tumor growth and enhancing immunotherapy. Its m6A-dependent mechanism involves regulating immune evasion, offering a new therapeutic target for CRC.

Area of Science:

  • Molecular Biology
  • Oncology
  • Immunotherapy

Background:

  • Non-coding RNAs (ncRNAs) play crucial regulatory roles in cancer, analogous to oncogenes and tumor suppressors.
  • A novel, pan-cancer downexpressed ncRNA, PANC754, was previously identified, but its function in colorectal cancer (CRC) remained unclear.

Purpose of the Study:

  • To elucidate the function and underlying molecular mechanism of PANC754 in colorectal cancer (CRC).
  • To investigate the potential of PANC754 as a therapeutic target, particularly in combination with immune checkpoint inhibitors.

Main Methods:

  • In vitro and in vivo experiments, including loss-of-function and gain-of-function studies.
  • Molecular docking, bioinformatic analysis, and co-culture systems were employed.
  • Investigated PANC754's interaction with METTL3, PSPC1, H3K4me1, and its effect on LGALS7 expression and immune checkpoint blockade.

Main Results:

  • Overexpressed PANC754 significantly inhibited CRC cell viability, migration, metastasis, and induced apoptosis.
  • PANC754, a nuclear-located ncRNA, is regulated by m6A modification via METTL3 and forms a complex with PSPC1 and H3K4me1.
  • This complex suppresses the immune evasive molecule LGALS7, enhancing the efficacy of anti-NKG2A (monalizumab) immunotherapy in CRC.

Conclusions:

  • PANC754 acts as a tumor-suppressing ncRNA in CRC through an m6A-dependent mechanism involving a novel ncRNA/RBP/histone repression complex.
  • PANC754 enhances immune checkpoint blockade (ICB) therapy by downregulating LGALS7, thereby improving NK and CTL cell-mediated tumor killing.
  • PANC754 represents a promising therapeutic target for improving immunotherapy outcomes in colorectal cancer.

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