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Cancers
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Involvement of RNA Polymerases I and III in Cancer Progression
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Involvement of RNA Polymerases I and III in Cancer Progression

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 13553

Special Issue Editor

Prof. Dr. Robert J. White

E-Mail Website
Guest Editor
Department of Biology, University of York, York YO10 5DD, UK
Interests: cancer; industrial biotechnology; RNA polymerase III; transcription; tRNA genes
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

Active synthesis of rRNA and tRNA by RNA polymerases (pols) I and III is a fundamental determinant of a cell’s capacity to grow. Most if not all cancers are likely to express abnormal levels of rRNAs and tRNAs. Multiple molecular mechanisms have been shown to contribute to this deregulation, including aberrant expression of specific transcription factors, activation of oncogenic signaling pathways, direct targeting by oncogene products, and loss of restraint by key tumour suppressors. Far less is known about the consequences of these changes, although a growing body of evidence has implicated specific tRNAs in promoting metastasis. Furthermore, deep sequencing of cancer genomes on a massive scale has implicated in tumorigenesis several other noncoding RNA genes that are transcribed by pol III, such as the RMRP gene. Strategies to manipulate pol III as a therapeutic target remain at early preclinical stages, but a specific inhibitor of pol I has reached clinical trials for solid and haematological malignancies.

This Special Issue aims to consider the involvement of pols I and III in cancer initiation, progression, and maintenance, including the roles of their individual ncRNA products. Related topics of relevance include the molecular mechanisms responsible for aberrant function of pols I and III in tumours and the potential of targeting these essential enzymes for therapeutic intervention.

Prof. Dr. Robert J. White
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cancer
  • RNA polymerase I
  • RNA polymerase III
  • rRNA
  • tRNA

Published Papers (6 papers)

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Research

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24 pages, 5681 KiB  
Article
A Combinatorial Regulatory Platform Determines Expression of RNA Polymerase III Subunit RPC7α (POLR3G) in Cancer
by Ruiying Cheng, Sihang Zhou, Rajendra K C, Simon Lizarazo, Leela Mouli, Anshita Jayanth, Qing Liu and Kevin Van Bortle
Cancers 2023, 15(20), 4995; https://doi.org/10.3390/cancers15204995 - 15 Oct 2023
Cited by 1 | Viewed by 2137
Abstract
RNA polymerase III (Pol III) subunit RPC7α, which is encoded by POLR3G in humans, has been linked to both tumor growth and metastasis. Accordantly, high POLR3G expression is a negative prognostic factor in multiple cancer subtypes. To date, the mechanisms underlying POLR3G upregulation [...] Read more.
RNA polymerase III (Pol III) subunit RPC7α, which is encoded by POLR3G in humans, has been linked to both tumor growth and metastasis. Accordantly, high POLR3G expression is a negative prognostic factor in multiple cancer subtypes. To date, the mechanisms underlying POLR3G upregulation have remained poorly defined. We performed a large-scale genomic survey of mRNA and chromatin signatures to predict drivers of POLR3G expression in cancer. Our survey uncovers positive determinants of POLR3G expression, including a gene-internal super-enhancer bound with multiple transcription factors (TFs) that promote POLR3G expression, as well as negative determinants that include gene-internal DNA methylation, retinoic-acid induced differentiation, and MXD4-mediated disruption of POLR3G expression. We show that novel TFs identified in our survey, including ZNF131 and ZNF207, functionally enhance POLR3G expression, whereas MXD4 likely obstructs MYC-driven expression of POLR3G and other growth-related genes. Integration of chromatin architecture and gene regulatory signatures identifies additional factors, including histone demethylase KDM5B, as likely influencers of POLR3G gene activity. Taken together, our findings support a model in which POLR3G expression is determined with multiple factors and dynamic regulatory programs, expanding our understanding of the circuitry underlying POLR3G upregulation and downstream consequences in cancer. Full article
(This article belongs to the Special Issue Involvement of RNA Polymerases I and III in Cancer Progression)
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25 pages, 10841 KiB  
Article
Selection of tRNA Genes in Human Breast Tumours Varies Substantially between Individuals
by Sienna P. Butterfield, Rebecca E. Sizer, Emma Rand and Robert J. White
Cancers 2023, 15(14), 3576; https://doi.org/10.3390/cancers15143576 - 12 Jul 2023
Cited by 2 | Viewed by 1432
Abstract
Abnormally elevated expression of tRNA is a common feature of breast tumours. Rather than a uniform increase in all tRNAs, some are deregulated more strongly than others. Elevation of particular tRNAs has been associated with poor prognosis for patients, and experimental models have [...] Read more.
Abnormally elevated expression of tRNA is a common feature of breast tumours. Rather than a uniform increase in all tRNAs, some are deregulated more strongly than others. Elevation of particular tRNAs has been associated with poor prognosis for patients, and experimental models have demonstrated the ability of some tRNAs to promote proliferation or metastasis. Each tRNA isoacceptor is encoded redundantly by multiple genes, which are commonly dispersed across several chromosomes. An unanswered question is whether the consistently high expression of a tRNA in a cancer type reflects the consistent activation of the same members of a gene family, or whether different family members are activated from one patient to the next. To address this question, we interrogated ChIP-seq data to determine which tRNA genes were active in individual breast tumours. This revealed that distinct sets of tRNA genes become activated in individual cancers, whereas there is much less variation in the expression patterns of families. Several pathways have been described that are likely to contribute to increases in tRNA gene transcription in breast tumours, but none of these can adequately explain the observed variation in the choice of genes between tumours. Current models may therefore lack at least one level of regulation. Full article
(This article belongs to the Special Issue Involvement of RNA Polymerases I and III in Cancer Progression)
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19 pages, 3180 KiB  
Article
Inhibition of RNA Polymerase III Augments the Anti-Cancer Properties of TNFα
by Hitha Gopalan Nair, Aneta Jurkiewicz and Damian Graczyk
Cancers 2023, 15(5), 1495; https://doi.org/10.3390/cancers15051495 - 27 Feb 2023
Viewed by 1726
Abstract
Tumour necrosis factor alpha (TNFα) is a multifunctional cytokine that plays a pivotal role in apoptosis, cell survival, as well as in inflammation and immunity. Although named for its antitumor properties, TNFα also has tumour-promoting properties. TNFα is often present in large quantities [...] Read more.
Tumour necrosis factor alpha (TNFα) is a multifunctional cytokine that plays a pivotal role in apoptosis, cell survival, as well as in inflammation and immunity. Although named for its antitumor properties, TNFα also has tumour-promoting properties. TNFα is often present in large quantities in tumours, and cancer cells frequently acquire resistance to this cytokine. Consequently, TNFα may increase the proliferation and metastatic potential of cancer cells. Furthermore, the TNFα-driven increase in metastasis is a result of the ability of this cytokine to induce the epithelial-to-mesenchymal transition (EMT). Overcoming the resistance of cancer cells to TNFα may have a potential therapeutic benefit. NF-κB is a crucial transcription factor mediating inflammatory signals and has a wide-ranging role in tumour progression. NF-κB is strongly activated in response to TNFα and contributes to cell survival and proliferation. The pro-inflammatory and pro-survival function of NF-κB can be disrupted by blocking macromolecule synthesis (transcription, translation). Consistently, inhibition of transcription or translation strongly sensitises cells to TNFα-induced cell death. RNA polymerase III (Pol III) synthesises several essential components of the protein biosynthetic machinery, such as tRNA, 5S rRNA, and 7SL RNA. No studies, however, directly explored the possibility that specific inhibition of Pol III activity sensitises cancer cells to TNFα. Here we show that in colorectal cancer cells, Pol III inhibition augments the cytotoxic and cytostatic effects of TNFα. Pol III inhibition enhances TNFα-induced apoptosis and also blocks TNFα-induced EMT. Concomitantly, we observe alterations in the levels of proteins related to proliferation, migration, and EMT. Finally, our data show that Pol III inhibition is associated with lower NF-κB activation upon TNFα treatment, thus potentially suggesting the mechanism of Pol III inhibition-driven sensitisation of cancer cells to this cytokine. Full article
(This article belongs to the Special Issue Involvement of RNA Polymerases I and III in Cancer Progression)
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21 pages, 5396 KiB  
Article
The POLR3G Subunit of Human RNA Polymerase III Regulates Tumorigenesis and Metastasis in Triple-Negative Breast Cancer
by Wiebke Lautré, Elodie Richard, Jean-Paul Feugeas, Hélène Dumay-Odelot and Martin Teichmann
Cancers 2022, 14(23), 5732; https://doi.org/10.3390/cancers14235732 - 22 Nov 2022
Cited by 8 | Viewed by 1847
Abstract
RNA polymerase (Pol) III transcribes short untranslated RNAs that contribute to the regulation of gene expression. Two isoforms of human Pol III have been described that differ by the presence of the POLR3G/RPC32α or POLR3GL/RPC32β subunits. POLR3G was found to be expressed in [...] Read more.
RNA polymerase (Pol) III transcribes short untranslated RNAs that contribute to the regulation of gene expression. Two isoforms of human Pol III have been described that differ by the presence of the POLR3G/RPC32α or POLR3GL/RPC32β subunits. POLR3G was found to be expressed in embryonic stem cells and at least a subset of transformed cells, whereas POLR3GL shows a ubiquitous expression pattern. Here, we demonstrate that POLR3G is specifically overexpressed in clinical samples of triple-negative breast cancer (TNBC) but not in other molecular subtypes of breast cancer. POLR3G KO in the MDA-MB231 TNBC cell line dramatically reduces anchorage-independent growth and invasive capabilities in vitro. In addition, the POLR3G KO impairs tumor growth and metastasis formation of orthotopic xenografts in mice. Moreover, KO of POLR3G induces expression of the pioneer transcription factor FOXA1 and androgen receptor. In contrast, the POLR3G KO neither alters proliferation nor the expression of epithelial–mesenchymal transition marker genes. These data demonstrate that POLR3G expression is required for TNBC tumor growth, invasiveness and dissemination and that its deletion affects triple-negative breast cancer-specific gene expression. Full article
(This article belongs to the Special Issue Involvement of RNA Polymerases I and III in Cancer Progression)
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14 pages, 8790 KiB  
Article
RNA Polymerase I Is Uniquely Vulnerable to the Small-Molecule Inhibitor BMH-21
by Ruth Q. Jacobs, Kaila B. Fuller, Stephanie L. Cooper, Zachariah I. Carter, Marikki Laiho, Aaron L. Lucius and David A. Schneider
Cancers 2022, 14(22), 5544; https://doi.org/10.3390/cancers14225544 - 11 Nov 2022
Cited by 7 | Viewed by 2137
Abstract
Cancer cells require robust ribosome biogenesis to maintain rapid cell growth during tumorigenesis. Because RNA polymerase I (Pol I) transcription of the ribosomal DNA (rDNA) is the first and rate-limiting step of ribosome biogenesis, it has emerged as a promising anti-cancer target. Over [...] Read more.
Cancer cells require robust ribosome biogenesis to maintain rapid cell growth during tumorigenesis. Because RNA polymerase I (Pol I) transcription of the ribosomal DNA (rDNA) is the first and rate-limiting step of ribosome biogenesis, it has emerged as a promising anti-cancer target. Over the last decade, novel cancer therapeutics targeting Pol I have progressed to clinical trials. BMH-21 is a first-in-class small molecule that inhibits Pol I transcription and represses cancer cell growth. Several recent studies have uncovered key mechanisms by which BMH-21 inhibits ribosome biosynthesis but the selectivity of BMH-21 for Pol I has not been directly measured. Here, we quantify the effects of BMH-21 on Pol I, RNA polymerase II (Pol II), and RNA polymerase III (Pol III) in vitro using purified components. We found that BMH-21 directly impairs nucleotide addition by Pol I, with no or modest effect on Pols II and III, respectively. Additionally, we found that BMH-21 does not affect the stability of any of the Pols’ elongation complexes. These data demonstrate that BMH-21 directly exploits unique vulnerabilities of Pol I. Full article
(This article belongs to the Special Issue Involvement of RNA Polymerases I and III in Cancer Progression)
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Review

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24 pages, 1456 KiB  
Review
Regulation of RNA Polymerase I Stability and Function
by Stephanie Pitts and Marikki Laiho
Cancers 2022, 14(23), 5776; https://doi.org/10.3390/cancers14235776 - 24 Nov 2022
Cited by 10 | Viewed by 2913
Abstract
RNA polymerase I is a highly processive enzyme with fast initiation and elongation rates. The structure of Pol I, with its in-built RNA cleavage ability and incorporation of subunits homologous to transcription factors, enables it to quickly and efficiently synthesize the enormous amount [...] Read more.
RNA polymerase I is a highly processive enzyme with fast initiation and elongation rates. The structure of Pol I, with its in-built RNA cleavage ability and incorporation of subunits homologous to transcription factors, enables it to quickly and efficiently synthesize the enormous amount of rRNA required for ribosome biogenesis. Each step of Pol I transcription is carefully controlled. However, cancers have highjacked these control points to switch the enzyme, and its transcription, on permanently. While this provides an exceptional benefit to cancer cells, it also creates a potential cancer therapeutic vulnerability. We review the current research on the regulation of Pol I transcription, and we discuss chemical biology efforts to develop new targeted agents against this process. Lastly, we highlight challenges that have arisen from the introduction of agents with promiscuous mechanisms of action and provide examples of agents with specificity and selectivity against Pol I. Full article
(This article belongs to the Special Issue Involvement of RNA Polymerases I and III in Cancer Progression)
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