RNA polymerase III transcription in cancer: the BRF2 connection
© Cabarcas and Schramm; licensee BioMed Central Ltd. 2011
Received: 13 December 2010
Accepted: 25 April 2011
Published: 25 April 2011
RNA polymerase (pol) III transcription is responsible for the transcription of small, untranslated RNAs involved in fundamental metabolic processes such mRNA processing (U6 snRNA) and translation (tRNAs). RNA pol III transcription contributes to the regulation of the biosynthetic capacity of a cell and a direct link exists between cancer cell proliferation and deregulation of RNA pol III transcription. Accurate transcription by RNA pol III requires TFIIIB, a known target of regulation by oncogenes and tumor suppressors. There have been significant advances in our understanding of how TFIIIB-mediated transcription is deregulated in a variety of cancers. Recently, BRF2, a component of TFIIIB required for gene external RNA pol III transcription, was identified as an oncogene in squamous cell carcinomas of the lung through integrative genomic analysis. In this review, we focus on recent advances demonstrating how BRF2-TFIIIB mediated transcription is regulated by tumor suppressors and oncogenes. Additionally, we present novel data further confirming the role of BRF2 as an oncogene, extracted from the Oncomine database, a cancer microarray database containing datasets derived from patient samples, providing evidence that BRF2 has the potential to be used as a biomarker for patients at risk for metastasis. This data further supports the idea that BRF2 may serve as a potential therapeutic target in a variety of cancers.
Cancer is a major health problem afflicting millions of Americans annually and despite tremendous research and treatment advances, is still the leading cause of death amongst men and women younger than age 85 years . A dominant characteristic of many types of cancer cells is its ability to proliferate uncontrollably. RNA polymerase (pol) III contains the largest number of subunits (17 subunits) and is responsible for the transcription of small, less than 300 nucleotides, untranslated RNAs involved in fundamental metabolic processes, such as RNA processing (U6 snRNA) and translation (tRNAs), which contribute to cell proliferation . Thus, deregulation of RNA pol III transcription can lead to aberrant production of critical RNAs contributing to uncontrolled cell growth, a hallmark trait of many types of cancer.
BRF2 (TFIIB-r elated f actor 2) shares structural features with TFIIB and BRF1 (Figure 1B). TFIIB, BRF1 and BRF2 all contain N-terminal zinc ribbon domains, core domains containing imperfect repeats; BRF1 and BRF2 have unrelated C-terminal extensions (Figure 1B) . The C-terminus of BRF2 is required for association with TBP and SNAPc (small nuclear activating protein complex) on the U6 promoter .
RNA pol III and cancer
Many different transformed cell types have been shown to have increased products of RNA pol III, when transformed by DNA tumor viruses, as well as chemical carcinogens [7–11] and their relevance has been validated in tumors of the breast, cervix, esophagus, lung, ovary, parotid, and tongue, but not in corresponding normal tissues tumors . Specifically, RT-PCR analysis has demonstrated that tRNAs are overproduced consistently in human ovarian cancers . Also, tRNA levels have been shown to be 10-fold higher in breast cancer cells than in normal cells . These increases are not simply a consequence of rapid cell proliferation in cancer , but instead contribute to tumorigenesis, as it has been demonstrated that overexpression of tRNAiMet induces proliferation and immortalization of fibroblasts .
Activation of TFIIIB activity has been noted in a variety of cancers types. Increased TBP expression has been observed in a clinically significant number of human colon cancers . Also, overexpression of BRF1 has also been shown to transform mouse embryo fibroblasts . Bdp1 is overexpressed in cells transformed by papovaviruses , but changes in expression levels in specific human cancer types have not been determined. Amplification of BRF2 has been noted in breast cancer [18, 19] and more recently a human bladder cancer cell line . Recently, Lockwood et al. demonstrated that genetic activation of BRF2 represents a unique mechanism of squamous cell carcinoma tumorigenesis, also providing the first clinical evidence implicating BRF2 as a novel lineage-specific oncogene in lung squamous cell carcinoma . This review will focus on BRF2-TFIIIB activity in cancer.
Regulation of BRF2-TFIIIB activity by oncogenes and tumor suppressors
RNA pol III transcription is tightly regulated during the cell cycle to ensure normal cellular growth . Cellular levels of RNA pol III are specifically increased in tissues isolated from mice with myeloma compared to tumor-free mice , directly linking RNA pol III activity and cancer. Recently, it was demonstrated that BRF1 and TBP are capable of driving oncogenic transformation [16, 23]. These observations demonstrate that elevation of RNA pol III transcription contributes to oncogenesis. TFIIIB activity is strictly regulated by Maf1 [24–27], chemopreventative agents , and oncogenes and tumor suppressors which are discussed below.
RB controls cell growth by preventing cell cycle entry in the absence of appropriate mitogenic signals and inactivation is associated with a variety of human cancers . RB regulates RNA pol III transcription by disrupting interactions between TFIIIB and RNA pol III [38, 46–49] RB-mediated repression of U6 transcription can be restored by recombinant SNAPc and TBP .
p53 is activated in response to cellular stress, inducing cell cycle arrest or apoptosis, and its inactivation is considered a critical step in carcinogenesis . p53 represses not only Alu and U6 transcription, but also tRNA, 5S rRNA, VAI, B2 and EBER (Epstein-Barr virus) transcription, establishing p53 as a general repressor of RNA pol III transcription . p53 regulates U6 transcription through interaction with the BRF2-TFIIIB subunit TBP  and SNAPc .
BRCA1 plays a role in DNA repair, cell cycle regulation, apoptosis, genome integrity and ubiquitination [52, 53]. Recently, BRCA1 has been characterized as a general repressor of RNA pol III transcription . BRF2 overexpression alleviates BRCA1 mediated repression of U6 transcription , suggesting that regulation of U6 transcription by BRCA1 occurs, in part, through BRF2. However, it is currently unclear whether the observed inhibition of RNA pol III transcription is a result of direct or indirect interactions between BRCA1 and BRF2, or BRCA1 and TFIIIB in general.
BRF2, a general oncogene?
It is established that RNA pol III is often deregulated in cancers [33–35] and specific elevation of RNA pol III transcripts and RNA pol III transcription factors such as U6 snRNA and BRF2 is a feature of both transformed cells and cancers . Recently, Lockwood et al identified BRF2 as a novel oncogene in lung squamous cell carcinoma demonstrating that overexpression of BRF2 can drive expression of RNA pol III transcripts contributing to squamous cell carcinoma tumorigenesis . However, it cannot currently be ruled out that TFIIIB, particularly the BRF2 subunit, could bind and potentially titrate tumor suppressors, thus alleviating some key mechanisms normally keeping TFIIIB activity in check, contributing to oncogenesis. Additionally, no Brf2-dependent pol III transcript has yet been shown to have transforming activity.
RNA pol III is a fundamental determinant of the capacity of a cell to grow and the identification of BRF2 as an oncogene further demonstrates the importance of proper regulation of RNA pol III transcription. Hence, we queried the Oncomine database to systematically assess gene expression levels of BRF2 in a variety of carcinomas. Oncomine is a bioinformatics initiative which collects, standardizes, analyzes, and delivers cancer transcriptome data to the biomedical research community . Rhodes et al. analysis of cancer transcriptome data has identified the genes, pathways, and networks deregulated across 18,000 cancer gene expression microarrays spanning 35 cancer types (for a comprehensive overview of the Oncomine database refer to ). Differential expression analysis is an important feature of the Oncomine resource. A unique feature of the Oncomine database is Oncomine automatically computes differential expression profiles for cancer types and subtypes allowing for simple query for individual gene expression.
Recently, RNA pol III transcription has been the focus of a Phase I and pharmacokinetic study. Hammond-Thelin et al. studied the effects of a novel nucleoside analog inhibitor (TAS-106) of RNA pol I, II and III, in patients with advanced solid malignancies . Previously, TAS-106 has demonstrated antitumor activity in various human cancer models including leukemic, lung, colorectal, stomach, pancreatic, and gastric cancers . The principal objectives of the study were to determine the maximum tolerated dose in patients, characterize the toxicities associated with TAS-106 administration, determine the pharmacokinetics of TAS-106 and study if there was any indication of antitumor activity in patients . Although this study is in its infancy, it's representative of the potential use of RNA pol III inhibitors as a means of pharmacological target for the treatment of cancers.
By elucidating the mechanism(s) by which RNA pol III transcription is both regulated and deregulated, it will be possible to further understand the mechanism(s) by which aberrant activity of the general transcription machinery contributes to cancer development. Deregulation of RNA pol III transcription in cancers coupled with the observation that TFIIIB, specifically BRF2-TFIIIB, is commonly a target of deregulation in a variety of cancers demonstrates that RNA pol III transcription is indeed a key player in tumorigenesis and could serve as a novel target in the development of pharmacological agents.
This work was supported in part by NIH grant 1R15CA133842-01A1 (LS). The authors wish to apologize, due to space restrictions, that not all TFIIIB studies could be mentioned. We thank Dr. Joby Jacob for his assistance with figure preparation.
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