Protein kinase R and its cellular regulators in cancer: An active player or a surveillant?

Lee, Yong Sun; Kunkeaw, Nawapol; Lee, Yeon-Su

doi:10.1002/wrna.1558

Cited by 38 publications

(45 citation statements)

References 224 publications

(374 reference statements)

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“…Remarkably, we identified immune and cytokine related terms for the genes co-regulated with vtRNA2-1. This association agrees with its proposed roles in innate immune modulation via PKR repression or OAS1 regulation and in cytokine production (Calderon and Conn, 2018;Golec et al, 2019;Lee et al, 2019b;Li et al, 2015). Furthermore, vtRNA2-1 has been associated with autoimmune disorders (Renauer et al, 2015;Weeding and Sawalha, 2018) and tumor engraftment in prostate cancer (Ma et al, 2020).…”

Section: Discussionsupporting

confidence: 78%

Pan-Cancer chromatin analysis of the human vtRNA genes uncovers their association with cancer biology

Fort

Duhagon

2020

Preprint

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The vault RNAs (vtRNAs) are a class of 84-141 nt eukaryotic non-coding RNAs transcribed by RNA polymerase III, named for their association with the conserved vault particle, a riboprotein complex whose function remains poorly understood. Of the 4 human vtRNA genes, the three clustered at locus 1, i.e. vtRNA1-1, vtRNA1-2 and vtRNA1-3, are integral components of the vault particle, while vtRNA2-1 is a more divergent homologue located in a second locus. Gene expression studies of vtRNAs in large cancer cohorts have been hindered by the failure of vtRNA sequencing using conventional transcriptomic approaches. However, since the vtRNAs transcription is regulated by DNA methylation, the analysis of the chromatin status of their promoters is a suitable surrogate approach to study their expression. Here we infer the landscape of vtRNA expression in cancer from the genome-wide DNA methylation (Illumina Infinium Human Methylation 450 K BeadChip) and chromatin accessibility (ATAC-seq) data of The Cancer Genome Atlas (TCGA). On average, vtRNA1-1 has the most accessible chromatin, followed by vtRNA1-2, vtRNA2-1 and vtRNA1-3. The correlation of the chromatin status of the vtRNA promoters and the binding sites of a common core of transcription factors stands for their transcriptional co-regulation by factors related to viral infection. Yet, vtRNA2-1 is the most independently regulated vtRNA homologue across tissue types. VtRNA1-1 and vtRNA1-3 chromatin status does not significantly change in cancer, though vtRNA1-3 promoter has repressive chromatin marks in a few cancer types. However, vtRNA2-1 and vtRNA1-2 expression are widely deregulated in neoplastic tissues and is compatible with a broad oncogenic role of vtRNA1-2, and both tumor suppressor and oncogenic functions of vtRNA2-1 depending of tissue contexts. Yet, vtRNA1-1, vtRNA1-2 and vtRNA2-1 promoter DNA methylation predicts a shorter patient overall survival cancer-wide. In addition, gene ontology analyses of co-regulated genes identifies a chromosome 5 regulatory domain controlling vtRNA1-1 and neighboring genes, and epithelial differentiation, immune and thyroid cancer gene sets for vtRNA1-2, vtRNA2-1 and vtRNA1-3 respectively. Furthermore, vtRNA expression patterns are associated with cancer immune subtypes. Finally, vtRNA1-2 expression is positively associated with cell proliferation and wound healing, in agreement with its oncogenic expression profile. Overall, our study presents the landscape of vtRNA expression cancer-wide, identifying co-regulated gene networks and ontological pathways associated with the different vtRNA genes that may account for their diverse roles in cancer.

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Section: Discussionsupporting

confidence: 78%

Pan-Cancer chromatin analysis of the human vtRNA genes uncovers their association with cancer biology

Fort

Duhagon

2020

Preprint

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“…Activated PKR can phosphorylate eIF2α (eukaryotic translation initiation factor 2) and thus inhibit global translation, leading to apoptosis. However, depending on the cell type and cellular context, it can also activate the NF-κB pathway, which favors cell proliferation (for review, see Lee et al 2019). In addition, PKR-independent functions of nc886 have been reported (Fig.…”

Section: Nc886mentioning

confidence: 99%

RNA polymerase III transcription as a disease factor

Yeganeh

Hernandez

2020

Genes Dev.

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RNA polymerase (Pol) III is responsible for transcription of different noncoding genes in eukaryotic cells, whose RNA products have well-defined functions in translation and other biological processes for some, and functions that remain to be defined for others. For all of them, however, new functions are being described. For example, Pol III products have been reported to regulate certain proteins such as protein kinase R (PKR) by direct association, to constitute the source of very short RNAs with regulatory roles in gene expression, or to control microRNA levels by sequestration. Consistent with these many functions, deregulation of Pol III transcribed genes is associated with a large variety of human disorders. Here we review different human diseases that have been linked to defects in the Pol III transcription apparatus or to Pol III products imbalance and discuss the possible underlying mechanisms.

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“…The role of PKR as a cellular stress response protein is widely known, as PKR intervenes against numerous and varied infections, also eliminating damaged cells inducing apoptosis. In addition, PKR is able to allow the cells to live via NF-kB activation once the stress has been resolved on time [4,7,8,13]. Moreover, PKR also regulates some tumour suppressors and protein kinases involved in cancer pathways such as the signal transducers and activators of transcription factors (STATs), activating transcription factors (ATFs), tumour suppressor p53 (Tp53), the phosphatase and tensin homologue tumour suppressor (PTEN), the mitogen-activated protein kinases (MAPKs), and the toll-like receptors (TLRs), among others [4,7,8,13].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, PKR is able to allow the cells to live via NF-kB activation once the stress has been resolved on time [4,7,8,13]. Moreover, PKR also regulates some tumour suppressors and protein kinases involved in cancer pathways such as the signal transducers and activators of transcription factors (STATs), activating transcription factors (ATFs), tumour suppressor p53 (Tp53), the phosphatase and tensin homologue tumour suppressor (PTEN), the mitogen-activated protein kinases (MAPKs), and the toll-like receptors (TLRs), among others [4,7,8,13]. All these data suggest how important it is that PKR is expressed at adequate levels in normal tissue where it would be slightly regulated, as well as the importance that PKR would have in tumours where, regardless of its expression, its regulation can be critical.…”

Section: Discussionmentioning

confidence: 99%

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Uncovering Tumour Heterogeneity through PKR and nc886 Analysis in Metastatic Colon Cancer Patients Treated with 5-FU-Based Chemotherapy

Ortega-García

Mesa

Moya

et al. 2020

Cancers

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Colorectal cancer treatment has advanced over the past decade. The drug 5-fluorouracil is still used with a wide percentage of patients who do not respond. Therefore, a challenge is the identification of predictive biomarkers. The protein kinase R (PKR also called EIF2AK2) and its regulator, the non-coding pre-mir-nc886, have multiple effects on cells in response to numerous types of stress, including chemotherapy. In this work, we performed an ambispective study with 197 metastatic colon cancer patients with unresectable metastases to determine the relative expression levels of both nc886 and PKR by qPCR, as well as the location of PKR by immunohistochemistry in tumour samples and healthy tissues (plasma and colon epithelium). As primary end point, the expression levels were related to the objective response to first-line chemotherapy following the response evaluation criteria in solid tumours (RECIST) and, as the second end point, with survival at 18 and 36 months. Hierarchical agglomerative clustering was performed to accommodate the heterogeneity and complexity of oncological patients' data. High expression levels of nc886 were related to the response to treatment and allowed to identify clusters of patients. Although the PKR Cancers 2020, 12, 379 2 of 17 mRNA expression was not associated with chemotherapy response, the absence of PKR location in the nucleolus was correlated with first-line chemotherapy response. Moreover, a relationship between survival and the expression of both PKR and nc886 in healthy tissues was found. Therefore, this work evaluated the best way to analyse the potential biomarkers PKR and nc886 in order to establish clusters of patients depending on the cancer outcomes using algorithms for complex and heterogeneous data.

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Protein kinase R and its cellular regulators in cancer: An active player or a surveillant?

Cited by 38 publications

References 224 publications

Pan-Cancer chromatin analysis of the human vtRNA genes uncovers their association with cancer biology

Pan-Cancer chromatin analysis of the human vtRNA genes uncovers their association with cancer biology

RNA polymerase III transcription as a disease factor

Uncovering Tumour Heterogeneity through PKR and nc886 Analysis in Metastatic Colon Cancer Patients Treated with 5-FU-Based Chemotherapy

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