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<p>Oral squamous cell carcinoma (OSCC) is an aggressive malignancy with poor prognosis and limited therapeutic options. N6-methyladenosine (m⁶A) modification has emerged as a key regulator of RNA fate, including circular RNAs (circRNAs), yet the functional contribution of m⁶A-modified circRNAs to OSCC remains incompletely defined. Here, we characterized hsa_circ_0002694, a previously unannotated circRNA, and investigated its m⁶A-associated regulatory mechanism in OSCC. We found that hsa_circ_0002694 was markedly upregulated in OSCC tissues and cell lines. Loss-of-function assays showed that hsa_circ_0002694 silencing inhibited OSCC cell proliferation, migration, and invasion in vitro and suppressed xenograft tumor growth in vivo. Mechanistically, METTL14-dependent m⁶A modification supported hsa_circ_0002694 abundance and enabled recognition/association by the nuclear m⁶A reader YTHDC1, contributing to its stability and nuclear retention/distribution. In the cytoplasm, hsa_circ_0002694 functioned as a competing endogenous RNA by sequestering miR-616-3p, thereby de-repressing METTL14 and reinforcing a putative positive feedback loop. In parallel, METTL14 increased m⁶A enrichment on MYC transcripts and, together with the m⁶A reader YTHDF1, promoted c-Myc protein expression, linking the circRNA circuit to an established oncogenic driver in OSCC. RNA immunoprecipitation, MeRIP-PCR, and RNA pull-down assays supported the m⁶A-associated regulatory relationships among hsa_circ_0002694, METTL14, YTHDC1, and miR-616-3p. Collectively, our findings define an m⁶A-regulated hsa_circ_0002694-centered network that connects METTL14/YTHDC1 control of circRNA fate with miR-616-3p-mediated de-repression and METTL14/YTHDF1-dependent c-Myc upregulation, providing mechanistic insight into epitranscriptomic circRNA regulation in OSCC and suggesting hsa_circ_0002694 as a potential biomarker and therapeutic target.</p>

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m⁶A-Modified hsa_circ_0002694 facilitates OSCC progression via the METTL14/YTHDC1/miR-616-3p/c-Myc axis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月9日

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  • Lina Liu,
  • Bo Xu,
  • Xin Leng,
  • Yixuan Li,
  • Jun Zhao,
  • Jie Wu,
  • Jiayin Deng,
  • Wensheng Ma

摘要

Oral squamous cell carcinoma (OSCC) is an aggressive malignancy with poor prognosis and limited therapeutic options. N6-methyladenosine (m⁶A) modification has emerged as a key regulator of RNA fate, including circular RNAs (circRNAs), yet the functional contribution of m⁶A-modified circRNAs to OSCC remains incompletely defined. Here, we characterized hsa_circ_0002694, a previously unannotated circRNA, and investigated its m⁶A-associated regulatory mechanism in OSCC. We found that hsa_circ_0002694 was markedly upregulated in OSCC tissues and cell lines. Loss-of-function assays showed that hsa_circ_0002694 silencing inhibited OSCC cell proliferation, migration, and invasion in vitro and suppressed xenograft tumor growth in vivo. Mechanistically, METTL14-dependent m⁶A modification supported hsa_circ_0002694 abundance and enabled recognition/association by the nuclear m⁶A reader YTHDC1, contributing to its stability and nuclear retention/distribution. In the cytoplasm, hsa_circ_0002694 functioned as a competing endogenous RNA by sequestering miR-616-3p, thereby de-repressing METTL14 and reinforcing a putative positive feedback loop. In parallel, METTL14 increased m⁶A enrichment on MYC transcripts and, together with the m⁶A reader YTHDF1, promoted c-Myc protein expression, linking the circRNA circuit to an established oncogenic driver in OSCC. RNA immunoprecipitation, MeRIP-PCR, and RNA pull-down assays supported the m⁶A-associated regulatory relationships among hsa_circ_0002694, METTL14, YTHDC1, and miR-616-3p. Collectively, our findings define an m⁶A-regulated hsa_circ_0002694-centered network that connects METTL14/YTHDC1 control of circRNA fate with miR-616-3p-mediated de-repression and METTL14/YTHDF1-dependent c-Myc upregulation, providing mechanistic insight into epitranscriptomic circRNA regulation in OSCC and suggesting hsa_circ_0002694 as a potential biomarker and therapeutic target.