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CircMET promotes tumor proliferation by enhancing CDKN2A mRNA decay and upregulating SMAD3

Lei Yang1,2, Yi Chen1,2, Ning Liu1,2

  • 1Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, 210093, Jiangsu, China.

Molecular Cancer
|January 19, 2022
PubMed
Abstract

Insights

Circular MET (circMET) promotes Xp11.2 translocation/NONO-TFE3 fusion renal cell carcinoma (tRCC) progression by regulating CDKN2A and SMAD3. CircMET may be a therapeutic target for tRCC and other cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Circular RNAs (circRNAs) play crucial roles in cancer, but the function of circMET (hsa_circ_0082002) remains unclear.
  • This study investigates circMET's role in Xp11.2 translocation/NONO-TFE3 fusion renal cell carcinoma (NONO-TFE3 tRCC), a subtype with upregulated circMET.

Purpose of the Study:

  • To elucidate the mechanism of circMET in NONO-TFE3 tRCC progression.
  • To investigate circMET's role in post-transcriptional regulation within this cancer type.

Main Methods:

  • Fluorescence in situ hybridization (FISH) and real-time PCR to assess circMET expression and localization.
  • Functional assays including proliferation, EdU staining, colony, and sphere formation assays.
  • Investigated regulatory mechanisms using luciferase assays, RNA immunoprecipitation (RIP), RNA pulldown, and targeted RNA demethylation systems.

Main Results:

  • CircMET is upregulated in NONO-TFE3 tRCC tissues and cells, driven by the NONO-TFE3 fusion.
  • Overexpression of circMET significantly promotes NONO-TFE3 tRCC growth.
  • Mechanistically, circMET is exported to the cytosol via YTHDC1 in an N6-methyladenosine (m6A)-dependent manner, enhances CDKN2A mRNA decay by interacting with YTHDF2, and sponges miR-1197 to inhibit SMAD3 expression.

Conclusions:

  • CircMET promotes NONO-TFE3 tRCC development by regulating both CDKN2A and SMAD3.
  • CircMET presents a potential novel therapeutic target for NONO-TFE3 tRCC and other cancers with high circMET expression.
Keywords:
CDKN2ANONO-TFE3SMAD3circMETm6A modification

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