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METTL14-mediated m6A modification of ZFP14 inhibits clear cell renal cell carcinoma progression via promoting STAT3

Zhuonan Liu1, Tianshui Sun2, Zhe Zhang1

  • 1Department of Urology, First Hospital of China Medical University, Shenyang City, Liaoning Province, China.

Clinical and Translational Medicine
|February 12, 2025
PubMed

Insights

Methyltransferase-like 14 (METTL14) targets zinc finger protein 14 (ZFP14) via m6A modification, suppressing clear cell renal cell carcinoma (ccRCC) progression. ZFP14 inhibits ccRCC by destabilizing STAT3 and reducing MMP1/3 levels.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Advanced clear cell renal cell carcinoma (ccRCC) lacks adequate therapeutic options.
  • Methyltransferase-like 14 (METTL14) is an enzyme involved in N6-methyladenosine (m6A) modification, previously shown to suppress ccRCC.
  • The precise molecular mechanisms of METTL14 in ccRCC require further elucidation.

Purpose of the Study:

  • To identify novel targets of METTL14-mediated m6A modification in ccRCC.
  • To investigate the role of zinc finger protein 14 (ZFP14) in ccRCC development and progression.
  • To elucidate the molecular mechanisms by which METTL14 and ZFP14 regulate ccRCC.

Main Methods:

  • Identified ZFP14 as a direct target of METTL14-mediated m6A modification.
  • Investigated the interaction between METTL14, ZFP14 mRNA, and insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2).
  • Assessed the functional impact of the METTL14/ZFP14 axis on ccRCC cell behavior in vitro and in vivo.
  • Examined the interaction between ZFP14 and signal transducer and activator of transcription 3 (STAT3), including ubiquitination and proteasomal degradation.

Main Results:

  • ZFP14 was identified as a novel METTL14 target, with its underexpression linked to ccRCC tumorigenesis and progression.
  • METTL14 promotes m6A modification of ZFP14 mRNA, enhancing its stability and expression via IGF2BP2.
  • The METTL14/ZFP14 axis suppressed ccRCC cell growth, migration, invasion, proliferation, and metastasis.
  • ZFP14 promotes STAT3 degradation through K48-linked ubiquitination and subsequent proteasomal degradation, inhibiting ccRCC progression and reducing MMP1/3 levels.

Conclusions:

  • ZFP14 is a novel target of METTL14-mediated m6A modification and acts as a significant tumor suppressor in ccRCC.
  • The METTL14/ZFP14/STAT3 pathway represents a potential therapeutic target for ccRCC treatment.
  • Understanding these molecular mechanisms provides insights into ccRCC pathogenesis and opens avenues for novel therapeutic strategies.
Keywords:
METTL14STAT3ZFP14ccRCCm6Aubiquitination

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