A Regulatory Noncoding RNA, nc886, Suppresses Esophageal Cancer by Inhibiting the AKT Pathway and Cell Cycle Progression

Im, Wonkyun Ronny; Hyun-Sung, Lee; Lee, Yeon-Su; Lee, Ju-Seog; Jang, Hee-Jin; Kim, Seon‐Young; Park, Jong‐Lyul; Lee, Yeontaek; Kim, Moon Soo; Lee, Jong Mog; Kim, In-Hoo; Jeon, Sung Ho; Lee, Yong Sun

doi:10.3390/cells9040801

Cited by 16 publications

(17 citation statements)

References 33 publications

(50 reference statements)

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“…Thus far, only a few fragmentary functions of the vault complex have been identified including the assembly of the nuclear pore complex [ 102 , 103 ] or roles in innate immunity [ 104 , 105 ]. It was reported that the expression levels of the vault complex components such as vtRNAs and MVP varied in several cancer cells [ 46 , 68 , 83 , 85 , 86 , 106 , 107 , 108 , 109 , 110 ]. Furthermore, the intracellular localization of the vault complex tends to be changed from the cytoplasm to the nucleus in response to external stresses or stimuli, which are involved in tumorigenesis [ 26 , 111 ].…”

Section: Mvp and The Vault Complex: Implications To Cell Proliferatio...mentioning

confidence: 99%

Small but Powerful: The Human Vault RNAs as Multifaceted Modulators of Pro-Survival Characteristics and Tumorigenesis

Gallo

Kong

Ferro

et al. 2022

Cancers

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The importance of non-coding RNAs for regulating gene expression has been uncovered in model systems spanning all three domains of life. More recently, their involvement in modulating signal transduction, cell proliferation, tumorigenesis and cancer progression has also made them promising tools and targets for oncotherapy. Recent studies revealed a class of highly conserved small ncRNAs, namely vault RNAs, as regulators of several cellular homeostasis mechanisms. The human genome encodes four vault RNA paralogs that share significant sequence and structural similarities, yet they seem to possess distinct roles in mammalian cells. The alteration of vault RNA expression levels has frequently been observed in cancer tissues, thus hinting at a putative role in orchestrating pro-survival characteristics. Over the last decade, significant advances have been achieved in clarifying the relationship between vault RNA and cellular mechanisms involved in cancer development. It became increasingly clear that vault RNAs are involved in controlling apoptosis, lysosome biogenesis and function, as well as autophagy in several malignant cell lines, most likely by modulating signaling pathways (e.g., the pro-survival MAPK cascade). In this review, we discuss the identified and known functions of the human vault RNAs in the context of cell proliferation, tumorigenesis and chemotherapy resistance.

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Section: Mvp and The Vault Complex: Implications To Cell Proliferatio...mentioning

confidence: 99%

Small but Powerful: The Human Vault RNAs as Multifaceted Modulators of Pro-Survival Characteristics and Tumorigenesis

Gallo

Kong

Ferro

et al. 2022

Cancers

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show abstract

“…Due to its importance for cancer biology, vtRNA2-1 transcriptional regulation was recently more investigated ( Yeganeh & Hernandez, 2020 ). Various studies reported tissue specific roles of vtRNA2-1 in normal ( Golec et al , 2019 ; Lee et al , 2019 ; Miñones-Moyano et al , 2013 ; Sallustio et al , 2016 ; Suojalehto et al , 2014 ) and cancer tissues ( Ahn et al , 2018 ; Fort et al , 2018 ; Hu et al , 2017 ; Im et al , 2020 ; Jeon et al , 2012a ; Kunkeaw et al , 2012 ; Lee et al , 2011 ; Lee, 2015 ; Lee et al , 2016 ; Lee et al , 2014a ; Lee et al , 2014b ; Lei et al , 2017 ; Li et al , 2017 ; Ma et al , 2020 ; Treppendahl et al , 2012 ) and epigenetic alterations of the locus have been described in different malignancies ( Ahn et al , 2018 ; Cao et al , 2013 ; Fort et al , 2018 ; Helbo et al , 2015 ; Helbo et al , 2017 ; Joo et al , 2018 ; Lee et al , 2014a ; Lee et al , 2014b ; Park et al , 2017a ; Romanelli et al , 2014 ; Treppendahl et al , 2012 ). Meanwhile, except for Kirsten Grønbæk group´s contributions on the chromatin characterization of vtRNA1-3 and vtRNA1-2 promoters ( Helbo et al , 2015 ; Helbo et al , 2017 ), little is known about the transcriptional regulation and expression of the other vtRNAs.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, vtRNA2-1 was proposed as a new type of ncRNA functioning as a tumor suppressor gene (TSG) that inhibits PKR, and was consequently renamed as “nc886” ( Golec et al , 2019 ; Jeon et al , 2012a ; Jeon et al , 2012b ; Lee et al , 2011 ). Then, its anti-proliferative and TSG function was described in prostate ( Aakula et al , 2016 ; Fort et al , 2018 ; Ma et al , 2020 ), skin ( Lee et al , 2019a ), gastric ( Lee et al , 2014b ) esophageal ( Im et al , 2020 ; Lee et al , 2014a ) and cholangiocarcinoma cells ( Kunkeaw et al , 2012 ). Conversely, a pro-proliferative and anti-apoptotic oncogenic role was proposed for vtRNA2-1 in renal ( Lei et al , 2017 ), ovarian ( Ahn et al , 2018 ), thyroid ( Lee et al , 2016 ), cervical ( Li et al , 2017 ) and endometrial ( Hu et al , 2017 ) tissues.…”

Section: Introductionmentioning

confidence: 99%

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

Fort

Duhagon

2021

F1000Res

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Background: The vault RNAs (vtRNAs) are a class of 84-141-nt eukaryotic non-coding RNAs transcribed by RNA polymerase III, associated to the ribonucleoprotein complex known as vault particle. Of the four human vtRNA genes, vtRNA1-1, vtRNA1-2 and vtRNA1-3, clustered at locus 1, 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 cohorts have been hindered by their unsuccessful sequencing using conventional transcriptomic approaches. Methods: VtRNA expression in The Cancer Genome Atlas (TCGA) Pan-Cancer cohort was estimated using the genome-wide DNA methylation and chromatin accessibility data (ATAC-seq) of their genes as surrogate variables. The association between vtRNA expression and patient clinical outcome, immune subtypes and transcriptionally co-regulated gene programs was analyzed in the dataset. Results: VtRNAs promoters are enriched in transcription factors related to viral infection. VtRNA2-1 is likely the most independently regulated homologue. VtRNA1-1 has the most accessible chromatin, followed by vtRNA1-2, vtRNA2-1 and vtRNA1-3. VtRNA1-1 and vtRNA1-3 chromatin status does not significantly change in cancer tissues. Meanwhile, vtRNA2-1 and vtRNA1-2 expression is widely deregulated in neoplastic tissues and its alteration is compatible with a broad oncogenic role for vtRNA1-2, and both tumor suppressor and oncogenic functions for vtRNA2-1. 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 vtRNAs co-regulated genes identify a chromosome regulatory domain, epithelial differentiation, immune and thyroid cancer gene sets for specific vtRNAs. Furthermore, vtRNA expression patterns are associated with cancer immune subtypes and vtRNA1-2 expression is positively associated with cell proliferation and wound healing. Conclusions: Our study presents the landscape of vtRNA chromatin status 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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“…Due to its importance for cancer biology, vtRNA2-1 transcriptional regulation was recently more investigated (Yeganeh and Hernandez, 2020). Various studies reported tissue specific roles of vtRNA2-1 in normal (Golec et al, 2019;Lee et al, 2019a;Miñones-Moyano et al, 2013;Sallustio et al, 2016;Suojalehto et al, 2014) and cancer tissue (Ahn et al, 2018;Fort et al, 2018;Hu et al, 2017;Im et al, 2020;Jeon et al, 2012a;Kunkeaw et al, 2012;Lee et al, 2011;Lee, 2015;Lee et al, 2016Lee et al, , 2014aLee et al, , 2014bLei et al, 2017;Li et al, 2017;Ma et al, 2020;Treppendahl et al, 2012) and epigenetic alterations of the locus have been described in different malignancies (Ahn et al, 2018;Cao et al, 2013;Fort et al, 2018;Helbo et al, 2015Helbo et al, , 2017Joo et al, 2018;Lee et al, 2014aLee et al, , 2014bPark et al, 2017;Romanelli et al, 2014;Treppendahl et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, vtRNA2-1 was proposed as a new type of ncRNA functioning as a tumor suppressor gene (TSG) that inhibits PKR, and was consequently renamed as "nc886" (Golec et al, 2019;Jeon et al, 2012aJeon et al, , 2012bLee et al, 2011). Then, its anti-proliferative and TSG function was described in prostate (Aakula et al, 2015;Fort et al, 2018;Ma et al, 2020), skin (Lee et al, 2019a), gastric (Lee et al, 2014b) and esophageal (Im et al, 2020;Lee et al, 2014a) and cholangiocarcinoma cells (Kunkeaw et al, 2012). Conversely, a pro-proliferative and anti-apoptotic oncogenic role was proposed for vtRNA2-1 in renal (Lei et al, 2017), ovarian (Ahn et al, 2018), thyroid (Lee et al, 2016), cervical (Li et al, 2017) and endometrial (Hu et al, 2017) tissues.…”

Section: Introductionmentioning

confidence: 99%

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.

show abstract

A Regulatory Noncoding RNA, nc886, Suppresses Esophageal Cancer by Inhibiting the AKT Pathway and Cell Cycle Progression

Cited by 16 publications

References 33 publications

Small but Powerful: The Human Vault RNAs as Multifaceted Modulators of Pro-Survival Characteristics and Tumorigenesis

Small but Powerful: The Human Vault RNAs as Multifaceted Modulators of Pro-Survival Characteristics and Tumorigenesis

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

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