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

Abstract

Colorectal cancer, one of the most commonly diagnosed cancers worldwide, is often accompanied by uncontrolled proliferation of tumor cells. Dyskerin pseudouridine synthase 1 (DKC1), screened using the genome-wide RNAi strategy, is a previously unidentified key regulator that promotes colorectal cancer cell proliferation. Enforced expression of DKC1, but not its catalytically inactive mutant D125A, accelerates cell growth in vitro and in vivo. DKC1 knockdown or its inhibitor pyrazofurin attenuates cell proliferation. Proteomics, RNA immunoprecipitation (RIP)-seq, and RNA decay analyses reveal that DKC1 binds to and stabilizes the mRNA of several ribosomal proteins (RPs), including RPL10A, RPL22L1, RPL34, and RPS3. DKC1 depletion significantly accelerates mRNA decay of these RPs, which mediates the oncogenic function of DKC1. Interestingly, these DKC1-regulated RPs also interact with HRAS and suppress the RAS/RAF/MEK/ERK pathway. Pyrazofurin and trametinib combination synergistically restrains colorectal cancer cell growth in vitro and in vivo. Furthermore, DKC1 is markedly upregulated in colorectal cancer tissues compared to adjacent normal tissues. Colorectal cancer patients with higher DKC1 expression has consistently poorer overall survival and progression-free survival outcomes. Taken together, these data suggest that DKC1 is an essential gene and candidate therapeutic target for colorectal cancer.

• Authors: Guangyan Kan, Ziyang Wang, Chunjie Sheng, Gong Chen, Chen Yao, Yizhi Mao, Shuai Chen
• Journal: Advanced science (Weinheim, Baden-Wurttemberg, Germany) (Adv Sci (Weinh)) Vol. 8 Issue 10 Pg. 2004344 (05 2021) ISSN: 2198-3844 [Electronic] Germany
• PMID: 34026451 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Advanced Science published by Wiley‐VCH GmbH.

Chemical References

• Amides
• Cell Cycle Proteins
• DKC1 protein, human
• Nuclear Proteins
• Protein Kinase Inhibitors
• Pyrazoles
• Pyridones
• Pyrimidinones
• Ribosomal Proteins
• trametinib
• pyrazofurin
• Ribose
• MAP2K2 protein, human
• MAP Kinase Kinase 1
• MAP Kinase Kinase 2
• MAP2K1 protein, human

Topics

• Amides (administration & dosage, pharmacology)
• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Cell Cycle Proteins (antagonists & inhibitors, genetics, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Colorectal Neoplasms (drug therapy, genetics, metabolism, pathology)
• Drug Synergism
• Female
• Humans
• MAP Kinase Kinase 1 (antagonists & inhibitors, genetics, metabolism)
• MAP Kinase Kinase 2 (antagonists & inhibitors, genetics, metabolism)
• Mice
• Mice, Inbred BALB C
• Nuclear Proteins (antagonists & inhibitors, genetics, metabolism)
• Protein Kinase Inhibitors (administration & dosage, pharmacology)
• Pyrazoles (administration & dosage, pharmacology)
• Pyridones (administration & dosage, pharmacology)
• Pyrimidinones (administration & dosage, pharmacology)
• Ribose (administration & dosage, pharmacology)
• Ribosomal Proteins (metabolism)
• Survival Rate
• Up-Regulation
• Xenograft Model Antitumor Assays