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Dual Inhibition of DKC1 and MEK1/2 Synergistically Restrains the Growth of Colorectal Cancer Cells

Guangyan Kan1, Ziyang Wang1, Chunjie Sheng1

  • 1State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Sun Yat-sen University Cancer Center Guangzhou Guangdong 510060 P. R. China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|May 24, 2021
PubMed

Insights

Dyskerin pseudouridine synthase 1 (DKC1) drives colorectal cancer growth by stabilizing ribosomal protein mRNAs. Inhibiting DKC1 or combining its inhibitor with trametinib shows therapeutic potential for colorectal cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Colorectal cancer (CRC) is a major global health concern characterized by uncontrolled tumor cell proliferation.
  • Identifying novel regulators of CRC cell growth is crucial for developing effective therapies.

Purpose of the Study:

  • To investigate the role of Dyskerin pseudouridine synthase 1 (DKC1) in colorectal cancer progression.
  • To explore DKC1 as a potential therapeutic target for CRC.

Main Methods:

  • Genome-wide RNA interference (RNAi) screening to identify key regulators.
  • In vitro and in vivo cell growth assays.
  • Proteomics, RNA immunoprecipitation (RIP)-seq, and RNA decay analyses.
  • Analysis of DKC1 expression in colorectal cancer tissues and correlation with patient survival outcomes.

Main Results:

  • DKC1 promotes colorectal cancer cell proliferation both in vitro and in vivo.
  • DKC1 stabilizes mRNAs of several ribosomal proteins (RPs), including RPL10A, RPL22L1, RPL34, and RPS3, and its depletion accelerates RP mRNA decay.
  • DKC1-regulated RPs interact with HRAS and suppress the RAS/RAF/MEK/ERK pathway.
  • DKC1 is upregulated in colorectal cancer tissues, and high DKC1 expression correlates with poorer patient survival.
  • Combination therapy of pyrazofurin (DKC1 inhibitor) and trametinib (MEK inhibitor) synergistically inhibits CRC cell growth.

Conclusions:

  • DKC1 is a critical oncogene that promotes colorectal cancer cell proliferation by regulating ribosomal protein mRNA stability.
  • DKC1 represents a promising therapeutic target for colorectal cancer treatment.
  • Combined inhibition of DKC1 and the RAS/RAF/MEK/ERK pathway may offer a synergistic therapeutic strategy.
Keywords:
MEK1/2dyskerin pseudouridine synthase 1pyrazofurinribosomal proteintrametinib

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