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.

Gene Expression-Based Predication of RNA Pseudouridine Modification in Tumor Microenvironment and Prognosis of Glioma Patients

“…Although the relationship between elevated Ψ level and imbalance of pseudouridine synthases remains to be elucidated, performing transcriptomic analysis of Ψ synthases and evaluating Ψ levels in the blood, urine or tissue of patients in relevant clinical characteristics such as WHO grade, IDH status, may greatly aid in identifying the differences between gliomas of various clinicopathological parameters, and potentially promote the diagnosis and treatment of glioma. Notably, the DKC1 inhibitor pyrazofurin and the MEK1/2 inhibitor trametinib can synergistically suppress colorectal cancer growth, suggesting the Ψ synthases are very promising therapeutic targets for cancer ( Kan et al, 2021 ). 5-Fluorouracil (5-FU), the most widely used fluorinated pyrimidine in cancer treatment ( Gmeiner, 2020 ), has been shown to inhibit pseudouridine synthases.…”

“…The abnormality of Ψ modification is associated with various diseases. For instance, DKC1 stabilizes the mRNA of some ribosomal proteins depending on its pseudouridine synthase activity, thereby promoting colorectal cancer progression in vitro and in vivo ( Kan et al, 2021 ). Increasing evidences have suggested an association between abnormal expression of Ψ synthases (such as PUS1, PUS7, PUS10 and DKC1) and tumor malignant progression ( Jana et al, 2017 ; Elsharawy et al, 2020 ; Du et al, 2021 ; Stockert et al, 2021 ).…”

“…Increasing evidences have suggested an association between abnormal expression of Ψ synthases (such as PUS1, PUS7, PUS10 and DKC1) and tumor malignant progression ( Jana et al, 2017 ; Elsharawy et al, 2020 ; Du et al, 2021 ; Stockert et al, 2021 ). In addition, Ψ synthase inhibitors have been shown to repress tumor growth ( Gmeiner, 2020 ; Kan et al, 2021 ). However, the activity of Ψ synthases remains unclear in glioma.…”

Significant impact of mTORC1 and ATF4 pathways in CHO cell recombinant protein production induced by CDK4/6 inhibitor

“…It would be interesting to know if the reduction of RPL22L1 could alter the ribosome composition to enable formation of a specialized ribosome (Xue & Barna, 2012) that modulates translation of specific proteins such as the recombinant proteins in the CHO cells. We also noted that DKC1, which stabilizes RPL22L1 mRNA (Kan et al, 2021) had a transient change in phosphorylation at 3 h post-CCI treatment (Figure 3d). It would thus be interesting to know if DKC1 phosphorylation plays a role in modulating RPL22L1 level.…”

Advances in RNA Epigenetic Modifications in Hepatocellular Carcinoma and Potential Targeted Intervention Strategies

“…In all cases, pyrazofurin showed no efficient anticancer activity. However, since the expression level of DKC1 is not considered, it is unknown whether pyrazofurin can treat cancer patients with DKC1 overexpression (Kan et al, 2021). Floresta et al (2018) hypothesized and discovered that nucleoside analogs such as isoxazolidinyl derivative 5 -monophosphate have higher ligand efficiency in the enzyme active site than the natural substrate.…”