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Knockdown of YAP1 Reduces YTHDF3 to Stabilize SMAD7 and thus Inhibit Bladder Cancer Stem Cell Stemness

Dandan Qiu1, Lingling Gao2, Xingwei Yu1

  • 1Department of Urology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), 310000 Hangzhou, Zhejiang, China.

Discovery Medicine
|July 26, 2024
PubMed
Abstract

Insights

Yes-associated protein 1 (YAP1) silencing in bladder cancer stem cells (BCSCs) inhibits YTH domain-containing family protein 3 (YTHDF3)-mediated degradation of m6A-modified SMAD7. This leads to reduced cell stemness and tumor progression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Stem Cell Research

Background:

  • Previous studies established the oncogenic role of Yes-associated protein 1 (YAP1) in bladder cancer (BLCA).
  • This research investigates YAP1's specific impact on bladder cancer stem cells (BCSCs) and its underlying molecular mechanisms.

Purpose of the Study:

  • To elucidate the role of YAP1 in regulating the stemness and progression of bladder cancer stem cells (BCSCs).
  • To identify the molecular pathways, including N6-methyladenosine (m6A) modification and protein interactions, involved in YAP1's function in BCSCs.

Main Methods:

  • Bladder cancer stem cells (BCSCs) were isolated and characterized by CD133 expression.
  • Bioinformatic analysis identified YAP1 interacting proteins and the m6A site on SMAD7.
  • Experiments involved gene silencing (YAP1), overexpression (YTHDF3), and molecular assays (MeRIP, RIP, qRT-PCR, Western blot) to assess gene expression, protein interactions, and m6A modification levels.
  • Functional assays included proliferation (BrdU), migration/invasion (Transwell), and tumor sphere formation assays.

Main Results:

  • BCSCs exhibited higher stemness markers, YAP1, YTHDF3, TGF-β1 expression, and enhanced invasive capabilities compared to parental BLCA cells, with lower SMAD7 expression.
  • YAP1 knockdown reduced SMAD7 m6A levels and YTHDF3-SMAD7 interaction.
  • Silencing YAP1 inhibited BCSC proliferation, migration, invasion, and tumor sphere formation, while increasing SMAD7 expression. This effect was reversed by YTHDF3 overexpression.

Conclusions:

  • YAP1 plays a crucial role in maintaining bladder cancer stemness.
  • YAP1 silencing disrupts the YTHDF3-mediated degradation of m6A-modified SMAD7, thereby reducing BCSCs stemness and potential for tumor progression.
Keywords:
YAP1YTHDF3bladder cancerm6A methylationstemness

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