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<p>The advancement of clear cell renal cell carcinoma (ccRCC) is a significant problem in clinical practice, and understanding the molecular determinants of malignancy progression is essential for the creation of viable treatment targets. METTL16, a methyltransferase enzyme responsible for RNA modifications, has been linked to a variety of cancers. However, its specific role in ccRCC remain unclear. The function of METTL16 was validated using in vivo and in vitro gain/loss of function experiments. Our functional assays indicated that silencing METTL16 significantly impaired cell proliferation, migration, and invasive capabilities. Mechanistically, MeRIP-PCR and luciferase assays confirmed that METTL16 promoted m6A modification of KLK4 and enhanced its stability through recognition of the m6A reader protein, IGF2BP2. KLK4 overexpression reversed the proliferation and migration defects caused by METTL16 knockdown, possibly through activation of ERK and AKT signaling pathways. In vivo experiments further demonstrated that KLK4 overexpression mitigated tumor growth inhibition caused by METTL16 depletion. These findings suggest that METTL16 promotes ccRCC progression via KLK4-mediated signaling, highlighting a potential therapeutic target.</p>

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METTL16 promotes progression of clear cell renal cell carcinoma via up-regulating N6-methyladenosine modification of KLK4 mRNA

  • 期刊论文

  • 发表日期：

    2025年7月8日

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  • Bo Fan,
  • Yunfeng Niu,
  • Tao Li,
  • Hao Chen,
  • Kunpeng Zeng,
  • Shujun Li,
  • Yongliang Ma

摘要

The advancement of clear cell renal cell carcinoma (ccRCC) is a significant problem in clinical practice, and understanding the molecular determinants of malignancy progression is essential for the creation of viable treatment targets. METTL16, a methyltransferase enzyme responsible for RNA modifications, has been linked to a variety of cancers. However, its specific role in ccRCC remain unclear. The function of METTL16 was validated using in vivo and in vitro gain/loss of function experiments. Our functional assays indicated that silencing METTL16 significantly impaired cell proliferation, migration, and invasive capabilities. Mechanistically, MeRIP-PCR and luciferase assays confirmed that METTL16 promoted m6A modification of KLK4 and enhanced its stability through recognition of the m6A reader protein, IGF2BP2. KLK4 overexpression reversed the proliferation and migration defects caused by METTL16 knockdown, possibly through activation of ERK and AKT signaling pathways. In vivo experiments further demonstrated that KLK4 overexpression mitigated tumor growth inhibition caused by METTL16 depletion. These findings suggest that METTL16 promotes ccRCC progression via KLK4-mediated signaling, highlighting a potential therapeutic target.