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Decitabine Enhances Sorafenib Sensitivity in Renal Cell Carcinoma by Promoting BIN1 and SYNE1 Expressions

Lijie Kang1, Mengyun Jin1, Yuqin Mao1

  • 1Department of Pharmacy, Shaoxing People's Hospital, 312000 Shaoxing, Zhejiang, China.

Frontiers in Bioscience (Landmark Edition)
|October 30, 2024
PubMed
Abstract

Insights

Decitabine enhances bridging integrator 1 (BIN1) and spectrin repeat containing nuclear envelope protein 1 (SYNE1) expression, overcoming sorafenib resistance in clear cell renal cell carcinoma (ccRCC). This improves response to vascular endothelial growth factor pathway-targeting tyrosine kinase inhibitors (TKIs).

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Clear cell renal cell carcinoma (ccRCC) presents poor outcomes in advanced stages.
  • Resistance to vascular endothelial growth factor (VEGF) pathway-targeting tyrosine kinase inhibitors (TKIs) is a significant challenge in ccRCC treatment.

Purpose of the Study:

  • To investigate the role of decitabine in modulating bridging integrator 1 (BIN1) and spectrin repeat containing nuclear envelope protein 1 (SYNE1) expression.
  • To determine the impact of BIN1 and SYNE1 on ccRCC resistance to sorafenib.

Main Methods:

  • Bioinformatics analysis of datasets GSE64052 and CancerSea to identify TKI resistance-related genes, focusing on SYNE1.
  • Quantitative real-time PCR (qRT-PCR) and Western blot to assess gene and protein expression.
  • Cell counting kit-8 (CCK-8) assays and flow cytometry for cell viability and apoptosis analysis.
  • Co-Immunoprecipitation (Co-IP) and Glutathione-S-transferase (GST) Pull-down assays to confirm protein interactions.

Main Results:

  • SYNE1 was downregulated in sorafenib-resistant ccRCC cells; its overexpression increased sensitivity, reduced viability, and enhanced apoptosis.
  • A confirmed interaction between BIN1 and SYNE1, with lower BIN1 levels in resistant cells.
  • Decitabine treatment upregulated both SYNE1 and BIN1, promoting apoptosis and reducing sorafenib resistance.

Conclusions:

  • SYNE1 modulates sorafenib resistance in ccRCC via interaction with BIN1.
  • Decitabine enhances SYNE1 and BIN1 expression, improving TKI response.
  • This suggests decitabine as a potential strategy to overcome ccRCC resistance and improve patient outcomes.
Keywords:
bridging integrator 1clear cell renal cell carcinomadecitabinesorafenibspectrin repeat containing nuclear envelope protein 1

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