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YTHDC1 is downregulated by the YY1/HDAC2 complex and controls the sensitivity of ccRCC to sunitinib by targeting the

Wei Li1,2, Kun Ye1,2, Xurui Li1,2

  • 1Department of Urology, The Second Xiangya Hospital, Central South University, 410011, Changsha, Hunan, China.

Journal of Experimental & Clinical Cancer Research : CR
|August 16, 2022
PubMed
Abstract

Insights

YTHDC1, a key RNA-binding protein, is downregulated in clear cell renal cell carcinoma (ccRCC), hindering sunitinib treatment effectiveness. Targeting the YY1/HDAC2/YTHDC1/ANXA1 axis can restore sensitivity to tyrosine kinase inhibitors in ccRCC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Clear cell renal cell carcinoma (ccRCC) is often treated with tyrosine kinase inhibitors (TKIs) like sunitinib.
  • Resistance to TKIs is a significant clinical challenge, particularly with prolonged treatment.
  • YTHDC1, a nuclear reader of m6A-modified mRNA, has an unclear role in renal cancer.

Purpose of the Study:

  • To investigate the role and mechanism of YTHDC1 in ccRCC progression and sensitivity to TKIs.
  • To identify molecular pathways involved in ccRCC development and TKI resistance.

Main Methods:

  • Analysis of YTHDC1 expression in ccRCC using The Cancer Genome Atlas (TCGA) data.
  • In vitro and in vivo assays (CCK-8, wound healing, Transwell, xenografts) to assess YTHDC1 function.
  • Molecular analyses including Western blot, RT-qPCR, RIP-qPCR, MeRIP-qPCR, and RNA-seq to elucidate the YY1/HDAC2/YTHDC1/ANXA1 axis.

Main Results:

  • YTHDC1 expression is downregulated in ccRCC tissues and associated with poor patient prognosis.
  • YTHDC1 inhibits ccRCC progression by downregulating the ANXA1/MAPK pathway.
  • The YTHDC1/ANXA1 axis influences ccRCC sensitivity to TKIs.
  • HDAC2 inhibitors, via the YY1/HDAC2 complex, resensitize ccRCC to TKIs.

Conclusions:

  • A novel YY1/HDAC2/YTHDC1/ANXA1 axis has been identified.
  • This axis plays a critical role in modulating ccRCC progression and chemosensitivity.
  • Targeting this axis offers a potential strategy to overcome TKI resistance in ccRCC.
Keywords:
ANXA1Clear cell renal cell carcinomaHDAC2/YY1SunitinibYTHDC1

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