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Updated: Jun 23, 2025

Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter
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RUVBL1/2 Blockade Targets YTHDF1 Activity to Suppress m6A-Dependent Oncogenic Translation and Colorectal

Danyu Chen1, Fenfen Ji1, Qiming Zhou1

  • 1Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.

Cancer Research
|June 20, 2024
PubMed

Insights

Overexpressed YTHDF1 in colorectal cancer drives resistance. Targeting RUVBL1/2 impairs YTHDF1-driven cancer growth by blocking oncogenic translation, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • N6-methyladenosine (m6A) RNA-binding protein YTHDF1 is overexpressed in colorectal cancer (CRC), contributing to chemotherapeutic resistance.
  • Identifying novel therapeutic targets in YTHDF1-high CRC is crucial for improving patient outcomes.

Purpose of the Study:

  • To identify druggable targets in YTHDF1-high colorectal cancer.
  • To elucidate the functional and mechanistic roles of RUVBL1 and RUVBL2 in YTHDF1-driven CRC.

Main Methods:

  • CRISPR/Cas9 screening to identify targets.
  • Analysis of patient samples for RUVBL1/2 expression and prognostic value.
  • Functional assays in cancer cells, organoids, and xenografts.
  • Coimmunoprecipitation, mass spectrometry, and ribosome sequencing.
  • Pharmacological inhibition and siRNA-mediated knockdown of RUVBL1/2.

Main Results:

  • CRISPR screening identified RUVBL1 and RUVBL2 as putative targets in YTHDF1-high CRC.
  • RUVBL1/2 are overexpressed in CRC and predict poor prognosis.
  • Loss of RUVBL1/2 selectively inhibits the growth of YTHDF1-high CRC cells, organoids, and xenografts.
  • YTHDF1 and RUVBL1/2 form a feedforward loop promoting oncogenic translation.
  • RUVBL1/2 inhibition via CB6644 or siRNAs arrests YTHDF1-expressing CRC growth.

Conclusions:

  • RUVBL1/2 are potential prognostic markers and druggable targets in YTHDF1-high colorectal cancer.
  • Targeting RUVBL1/2 disrupts YTHDF1-driven oncogenic translation and protein synthesis.
  • RUVBL1/2 inhibition represents a promising therapeutic strategy for YTHDF1-driven colorectal cancer.

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