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<p>The role of RNA N<sup>6</sup>-methyladenoine (m<sup>6</sup>A) eraser AlkB homologue 5 (ALKBH5) in colorectal cancer (CRC) stem cells (CSCs) is unclear. Here, we find that ALKBH5 expression positively correlates with CSC markers in CRC patients. ALKBH5 induces self-renewal and stemness markers in colorectal CSCs and patient-derived organoids (PDOs). Colon-stem cell specific <i>Alkbh5</i> knockin accelerates carcinogen-induced CRC, while tumorigenesis is attenuated in colon-stem cell specific <i>Alkbh5</i> knockout mice. Integrated RNA-seq, MeRIP-seq and Ribo-seq reveal FAM84A as an ALKBH5 target. ALKBH5 demethylates m<sup>6</sup>A-modified FAM84A mRNA, causing mRNA decay and reduced expression. Mechanistically, we show that FAM84A represses CSCs by interacting with β-catenin and promoting β-catenin ubiquitination and degradation. By boosting CSCs, ALKBH5 overexpression elicit chemoresistance in CSCs, PDOs and transgenic mice. Targeting of ALKBH5 by knockout or VNPs-siALKBH5 synergizes with chemotherapy to trigger tumor regression in CSCs-/PDOs-derived xenografts and ALKBH5 knockout mice. Together, we reveal that ALKBH5 is essential for colorectal CSCs and is a therapeutic target for overcoming CRC chemoresistance.</p>

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Targeting of the m6A eraser ALKBH5 suppresses stemness and chemoresistance of colorectal cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月13日

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  • Heming Zhou,
  • Huarong Chen,
  • Weixin Liu,
  • Cong Liang,
  • Shiyan Wang,
  • Kai Yuan,
  • Alvin Ho Kwan Cheung,
  • Yuet Wu,
  • Wei Kang,
  • Henley Cheung,
  • Yanqiang Ding,
  • Qinyao Wei,
  • Hao Su,
  • Tianhui Li,
  • Weimei Luo,
  • Sujun Chen,
  • Chi Chun Wong,
  • Jun Yu

摘要

The role of RNA N6-methyladenoine (m6A) eraser AlkB homologue 5 (ALKBH5) in colorectal cancer (CRC) stem cells (CSCs) is unclear. Here, we find that ALKBH5 expression positively correlates with CSC markers in CRC patients. ALKBH5 induces self-renewal and stemness markers in colorectal CSCs and patient-derived organoids (PDOs). Colon-stem cell specific Alkbh5 knockin accelerates carcinogen-induced CRC, while tumorigenesis is attenuated in colon-stem cell specific Alkbh5 knockout mice. Integrated RNA-seq, MeRIP-seq and Ribo-seq reveal FAM84A as an ALKBH5 target. ALKBH5 demethylates m6A-modified FAM84A mRNA, causing mRNA decay and reduced expression. Mechanistically, we show that FAM84A represses CSCs by interacting with β-catenin and promoting β-catenin ubiquitination and degradation. By boosting CSCs, ALKBH5 overexpression elicit chemoresistance in CSCs, PDOs and transgenic mice. Targeting of ALKBH5 by knockout or VNPs-siALKBH5 synergizes with chemotherapy to trigger tumor regression in CSCs-/PDOs-derived xenografts and ALKBH5 knockout mice. Together, we reveal that ALKBH5 is essential for colorectal CSCs and is a therapeutic target for overcoming CRC chemoresistance.