Review
Dual role of G-quadruplex in translocation renal cell carcinoma: Exploring plausible Cancer therapeutic innovation

https://doi.org/10.1016/j.bbagen.2020.129719Get rights and content

Highlights

  • Xp11.2 tRCCs a subset of RCC outlined by chromosomal translocations involving Xp11.2, harboring TFE3 fusion gene

  • TFE3 fusion gene is a hallmark of Xp11 tRCC. Targeting their expression could be potential therapeutic attempt in tRCC

  • G4 plays dual role in tRCC as G4 stabilization causes inhibition in cell proliferation as well genomic aberration

  • In silico study using different G4 analysis tools reveals the presence of PQS in both TFE3 fusion gene or transcript

  • Both stabilization and destabilization of G4 in fusion gene/transcript would be a promising approach in tRCC prevention

Abstract

Background

Renal Cell Carcinoma (RCC) is the ninth leading cause of death among kidney cancer. Xp11.2 translocation harboring TFE3 fusion proteins, act as an oncogene in translocation cancers that constitute the hallmark of translocation renal cell carcinoma (tRCC). G-quadruplex (G4), an alternative nucleic acid structure is an emerging and promising factor in cancer. The presence of G4 within the genome plays a pioneering role in cancer as it contributes to genomic aberration as well as inhibition in cell proliferation.

Scope of review

Here we discuss the link between G4 and tRCC. We compile the available information of G-quadruplex & propose their dual role in tRCC, suggesting both stabilization and destabilization of G-quadruplex could be considered targets for tRCC.

Major conclusions

Our in Silico analysis of TFE3 and their three fusions partner's PRCC, SFPQ, and ASPSCR1 discloses a few putative G4 forming sequences (PQS) in their corresponding fusion gene or fusion transcript. Stabilization of G4 structure within fusion gene/transcript can be of great use towards potential therapeutics targeting fusion protein derived oncogenesis, as G4 is a serious menace for DNA polymerization, transcription & translation. G-quadruplex at intron-2 of the TFE3 has been reported to mediate its translocation also. Both stabilization and destabilization of the G4 structure would be a promising approach in the suppression of cancerous cell proliferation.

General significance

Pioneering studies discovered the relevance of G4 in cancer therapy and explore our approaches towards therapeutic innovation against oncogenic fusion protein and tRCC. Selectively targeting G4 in oncogenic fusion transcript will emerge as potential druggable structures.

Introduction

Cancer marks as the second leading cause of death globally, affecting about 9.6 million deaths in 2018. About 1 in 6 deaths occur due to cancer worldwide. Previous studies have shown that the accumulation of several genetic alterations directly or indirectly controls cancer while types of such alterations are widely variable which makes cancer a highly comprehensive condition. Genetic alteration in turns causes oncogene activation, loss of tumor suppressor gene, truncated or fusion gene generation with oncogenic potential mediating altered cellular functions which induces a normal cell into a cancerous cell. Chromosomal aberration is a central facet of cancer cells. The exact mechanism behind such alteration is still not understood which further poses a continued challenge.

Renal Cell Carcinoma (RCC) is very rare and aggressive. Worldwide RCC is the ninth leading cause of death among kidney cancers, whose chances of incidence increases annually. According to the American Cancer Society report 2019, globally 73,820 adults (44,120 men and 29,700 women) were approximately diagnosed with kidney cancer in the United States only. This disease is rarely found in younger-onset (<45 years) but the average age of diagnosis is 64 years [American cancer society 2019]. RCC originates from epithelium tissues of renal tubules which could be characterized by clinical and histological phenotypes and detected by abdominal computerized tomography (CT) and ultrasounds. RCC categorized in 3 types i.e. ccRCC: Clear Cell RCC, a most common (70–80%), pRCC: Papillary RCC, 15–20% & cRCC: Chromophobe RCC, the rarest (approx 5%) [1].These three RCC subtypes have different Histological features (Fig. 1). Late presentation and resistance to hormonal therapy, chemotherapy, and radiotherapy make RCC poor prognostication. Currently, there is no clinically proven therapy for RCC; therefore, new therapeutic strategies are needed in improving the therapeutic approach for RCC [2]. The occurrence of RCC in males is 25% higher than females showing distinct sex differences in RCC incidence, suggests the possible role for sex hormones & their receptors in RCC progression [3]. RCC has been reported as a hormone-related condition. Several hormone signaling pathways were outlined in RCC as some steroid hormone and hormone receptors such as - gonadotropin-releasing hormone (GnRH), estrogen receptors (ER), thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), glucocorticoid receptors (GR), androgen receptors (AR), etc. were overexpressed in RCC while corticotrophin-releasing hormone, Vitamin D, and progesterone receptors are down-regulated in different subtypes of RCC [4]. These findings prompt to investigate the role of hormone and their receptors with great interest. Essentially targeting such hormone signaling pathways could be a progressive step towards RCC prevention research. Targeting the sex hormone receptor and their pathways possibly reveal the role of hormonal signaling behind the sexual disparities in RCC. Further experimental investigation for the role of steroid hormone in RCC may justify the molecular basis behind the hormone-related etiology in RCC.

Kidney carcinoma was sub-classified in Translocation renal cell carcinoma (tRCC) by WHO in 2004. tRCC has been associated with Xp11.2 translocation that is controlled by a novel promoter of the TFE3 gene, known as the TFE3 transcription factor gene. This cancer subgroup found to be at young-onset mostly [5]. Not only RCC, but TFE3 fusion protein (the result of translocation) associated with Alveolar Soft Part sarcoma also falls in the same category. TFE3 as a transcription factor is an important protein in normal genetic behavior while fusion variants of TFE3 alter the genetic expression.

Section snippets

TFE3

TFE3 (Transcription Factor E3) is one of the members of the microphthalmia Family (MiT) transcription factor, which binds and activates transcription of genes containing E-box sequences (5’-CANNTG-3′) in their promoter. The cytogenetic location of TFE3 is Xp11.23; the genomic view is represented in Fig. 2.

TFE3 protein consists of transcription activation domain (AD), basic helix-loop-helix domain (b-HLH), and a leucine zipper domain. b-HLH and leucine zipper domain of TFE3 form protein

G-quadruplex

G-quadruplex (G4) is a non-B-form of DNA secondary structure, composed of the four-stranded helical structure formed by hoogsteen hydrogen base pairing within repetitive 4 guanine tracts in DNA or RNA that undergoes either intra and inter-molecular folding to generate square planer structure G-quartet which further stacked on top of one another and forms four-stranded helical conformations of G4. This conformation stabilizes by the presence of cation in the center of each pair of G-quartet. The

Putative G-quadruplex sequences (PQS) prediction in target genes

Sequences of genes ASPSCR1 (NG_030375.2), PRCC (NG_008138.1), and TFE3 (NG_016297.2) was retrieved from NCBI database and SFPQ (ENSG00000116560) retrieved from Ensemble database, were analyzed for putative G4 sequence prediction by online tool QGRS Mapper, a web-based server. Parameters of QGRS Mapper analysis are Max length: 30, Min G-group: 3, loop size 0 to 36. QGRS Mapper predicted several PQS in all 4 gene sequences; among them, some sequences (both exon and intron regions) with high

Conclusion

Xp11 Chromosomal translocation is the cytogenetic characterization of translocation renal cell carcinoma, a predominant kidney cancer whose incidence rate and mortality rate rises continuously. While several therapies were offered for renal cell carcinoma it still remains insufficient because of the high chemo-resistant property of RCC with side effects of drugs. Temsirolimus & sunitinib are some drugs discovered against Xp11.2 translocation but their mode of action is still unknown. In the

Future perspective

Association of G4 with several diseases, including cancers, offer potential opportunity for targeted therapeutic intervention. Stabilization of such G4 structure within fusion transcript as well as their destabilization at translocation break-point supposed to be inhibiting fusion gene expression and translocation, respectively that could be a potential future direction for cancer research. The Discovery of novel G4 stabilizers and destabilizers with high efficiency should improve the

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

We acknowledge Dr. Chandana Basu Mallick, DBT Welcome Trust Fellow, Centre for Genetic Disorders, BHU for her critical reading and feedback on this manuscript. We also acknowledge the contributions of the various research groups towards the expansion of the G-quadruplex work. We sincerely try to include and refer all the works relevant to this review; any inadvertent failing is highly regretted.

This research did not receive any specific grant from funding agencies in the public, commercial, or

References (91)

  • S. Paramasivan et al.

    Circular dichroism of quadruplex DNAs: applications to structure, cation effects and ligand binding

    Methods

    (2007)
  • J.C. Darnell et al.

    Fragile X mental retardation protein targets G quartet mRNAs important for neuronal function

    Cell

    (2001)
  • R. Pattanayak et al.

    Interaction of KRAS G-quadruplex with natural polyphenols: A spectroscopic analysis with molecular modeling

    Int. J. Biol. Macromol.

    (2016)
  • S. Bonnal et al.

    A single internal ribosome entry site containing a G quartet RNA structure drives fibroblast growth factor 2 gene expression at four alternative translation initiation codons

    J. Biol. Chem.

    (2003)
  • S. Lammich et al.

    Translational repression of the disintegrin and metalloprotease ADAM10 by a stable G-quadruplex secondary structure in its 50-untranslated region

    Journal of Biological Chemistry

    (2011)
  • G. Mirihana Arachchilage et al.

    Stable G-quadruplex enabling sequences are selected against by the context-dependent codon bias

    Gene

    (2019)
  • S.P. Verma et al.

    G-quadruplex structure at intron 2 of TFE3 and its role in Xp11.2 translocation and splicing

    Biochim. Biophys. Acta Gen. Subj.

    (2018)
  • H. Ross et al.

    Xp11 Translocation Renal Cell Carcinoma

    Pathology Case Reviews

    (2010)
  • N.C. Bennett et al.

    Evaluation of steroid hormones and their receptors in development and progression of renal cell carcinoma

    J Kidney Cancer VHL

    (2014)
  • A.M. Czarnecka et al.

    Hormone signaling pathways as treatment targets in renal cell cancer (review)

    Int. J. Oncol.

    (2016)
  • A. Franzini et al.

    A Case of Renal Cancer with Tfe3 Gene Fusion in an Elderly Man

    Urologia Internationalis

    (2007)
  • H. Beckmann et al.

    The leucine zipper of TFE3 dictates helix-loop-helix dimerization specificity

    Genes Dev.

    (1991)
  • J.A. Martina et al.

    The nutrient-responsive transcription factor TFE3 promotes autophagy, lysosomal biogenesis, and clearance of cellular debris

    Science Signaling

    (2014)
  • R.M. Perera et al.

    Transcriptional control of autophagy–lysosome function drives pancreatic cancer metabolism

    Nature

    (2015)
  • N. Pastore et al.

    TFEB and TFE3 cooperate in the regulation of the innate immune response in activated macrophages

    Autophagy

    (2016)
  • Z. Yagil et al.

    Transcription factor E3, a major regulator of mast cell–mediated allergic response

    Journal of Allergy and Clinical Immunology

    (2012)
  • Y. Nakagawa et al.

    TFE3 transcriptionally activates hepatic IRS-2, participates in insulin signaling and ameliorates diabetes

    Nature Medicine

    (2005)
  • N. Salma et al.

    Transcription factor Tfe3 directly regulates Pgc-1alpha in muscle

    J. Cell. Physiol.

    (2015)
  • H. Iwasaki et al.

    TFE3 regulates muscle metabolic gene expression, increases glycogen stores, and enhances insulin sensitivity in mice

    American Journal of Physiology-Endocrinology and Metabolism

    (2012)
  • K.N. Weilbaecher et al.

    Age-resolving Osteopetrosis: A rat model implicating Microphthalmia and the related transcription factor TFE3

    J. Exp. Med.

    (1998)
  • Y. Fujimoto et al.

    TFE3 Controls Lipid Metabolism in Adipose Tissue of Male Mice by Suppressing Lipolysis and Thermogenesis

    Endocrinology

    (2013)
  • P.L. Sheridan et al.

    Activation of the HIV-1 enhancer by the LEF-1 HMG protein on nucleosome-assembled DNA in vitro

    Genes Dev.

    (1995)
  • K.M. Ford et al.

    (2012). Molecular regulation of vascular endothelial growth factor expression in the retinal pigment epithelium

    Mol. Vis.

    (2012)
  • M. Ladanyi et al.

    The der(17)t(X;17)(p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25

    Oncogene

    (2001)
  • A.J.F. Lazar et al.

    Angiogenesis-Promoting Gene Patterns in Alveolar Soft Part Sarcoma

    Clinical Cancer Research

    (2007)
  • P. Argani et al.

    A novel CLTC-TFE3 gene fusion in pediatric renal adenocarcinoma with t(X;17)(p11.2;q23)

    Oncogene

    (2003)
  • J. Clark et al.

    Fusion of splicing factor genes PSF and NonO (p54nrb) to the TFE3 gene in papillary renal cell carcinoma

    Oncogene

    (1997)
  • S. Sidhar

    The t(X;1)(p11.2;q21.2) translocation in papillary renal cell carcinoma fuses a novel gene PRCC to the TFE3 transcription factor gene

    Hum. Mol. Genet.

    (1996)
  • Y.M. Skalsky et al.

    PRCC, the commonest TFE3 fusion partner in papillary renal carcinoma is associated with pre-mRNA splicing factors

    Oncogene

    (2001)
  • M.J. Weterman et al.

    Nuclear localization and transactivating capacities of the papillary renal cell carcinoma-associated TFE3 and PRCC (fusion) proteins

    Oncogene

    (2000)
  • P. Argani et al.

    Xp11 Translocation Renal Cell Carcinoma in Adults: Expanded Clinical, Pathologic, and Genetic Spectrum

    The American Journal of Surgical Pathology

    (2007)
  • D. Rhodes et al.

    G-quadruplexes and their regulatory roles in biology

    Nucleic Acids Res.

    (2015)
  • O. Kikin et al.

    QGRS mapper: a web-based server for predicting G-quadruplexes in nucleotide sequences

    Nucleic Acids Res.

    (2006)
  • V.K. Yadav et al.

    QuadBase: genome-wide database of G4 DNA--occurrence and conservation in human, chimpanzee, mouse and rat promoters and 146 microbes

    Nucleic Acids Res.

    (2008)
  • A. Bedrat

    Re-evaluation of G-quadruplex propensity with G4Hunter

    Nucleic Acids Res.

    (2016)
  • Cited by (5)

    View full text