Chimeric Transcript Generated by cis-Splicing of Adjacent Genes Regulates Prostate Cancer Cell Proliferation

Zhang, Yanmei; Gong, Mei; Yuan, Huiling; Park, Hong G.; Frierson, Henry F.; Li, Hui

doi:10.1158/2159-8290.cd-12-0042

Cited by 145 publications

(178 citation statements)

References 28 publications

(35 reference statements)

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“…However, recent studies using next-generation sequencing have identified a recurrent nonreciprocal chimera involving SLC45A3 and ELK4 in prostate cancer by a cis-splicing mechanism without DNA-level rearrangement (20)(21)(22). In this study we discovered recurrent reciprocal chimeric transcripts between YPEL5 and PPP1CB genes in CLL using whole-transcriptome sequencing.…”

mentioning

confidence: 78%

Recurrent reciprocal RNA chimera involving YPEL5 and PPP1CB in chronic lymphocytic leukemia

Velusamy

Palanisamy

Kalyana-Sundaram

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults in the Western hemisphere. Tumor-specific chromosomal translocations, characteristic findings in several human malignancies that directly lead to malignant transformation, have not been identified in CLL. Using paired-end transcriptome sequencing, we identified recurrent and reciprocal RNA chimeras involving yippee like 5 (YPEL5) and serine/threonine-protein phosphatase PP1-beta-catalytic subunit (PPP1CB) in CLL. Two of seven index cases (28%) harbored the reciprocal RNA chimeras in our initial screening. Using quantitative real-time PCR (q real-time PCR), YPEL5/PPP1CB and PPP1CB/YPEL5 fusion transcripts were detected in 97 of 103 CLL samples (95%) but not in paired normal samples, benign lymphocytes, or various unrelated cancers. Whole-genome sequencing and Southern blotting demonstrated no evidence for a genomic fusion between YPEL5 and PPP1CB. YPEL5/PPP1CB chimera, when introduced into mammalian cells, expressed a truncated PPP1CB protein that demonstrated diminished phosphatase activity. PPP1CB silencing resulted in enhanced proliferation and colony formation of MEC1 and JVM3 cells, implying a role in the pathogenesis of mature B-cell leukemia. These studies uncover a potential role for recurrent RNA chimeras involving phosphatases in the pathogenesis of a common form of leukemia. chimera splicing | next-generation sequencing | serine/threonine phosphatase PP1-beta catalytic subunit | B-lymphoid malignancy B -cell chronic lymphocytic leukemia (B-CLL) is the most common form of leukemia in adults in Western countries (1). The most common recurrent cytogenetic abnormality in CLL is a deletion involving the 13q14.3 locus, which occurs in 50% of cases and targets miR-16-1, miR-15a, and DLEU2 (2-4). Twenty percent of CLLs exhibit trisomy 12 (5). Other recurrent abnormalities in CLL include del 11q22-23 (ATM) and 17p13 (targeting p53) (6, 7). Of clinical relevance, IgV mutational status and zeta-chain associated protein kinase-70 kD (ZAP-70) expression have been associated with distinct prognostic categories of B-CLL (8-10). Recently, mutations in NOTCH1 (12.2%), MYD88 (2.9%), and XPO1 (2.4%) have been identified using next-generation sequencing (11, 12). The NOTCH1 mutations occur more frequently in cases with unmutated variable regions of the Ig heavy chain genes, whereas the MYD88 mutations occur more frequently in mutated cases (11).Although the role of genomic events is well established in the pathogenesis of cancers, the contribution of posttranscriptional RNA processing, which plays a fundamental role in control of protein expression, is less well understood.Alternative splicing can affect the translation, localization, or degradation of mRNA (13) and frequently results in the production of multiple and functionally distinct protein isoforms (14). Importantly, alternative splicing and expression of abnormal splicing chimeras may contribute to cancer pathogenesis and are associated with prognostic significance (15, 16). For exam...

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confidence: 78%

Recurrent reciprocal RNA chimera involving YPEL5 and PPP1CB in chronic lymphocytic leukemia

Velusamy

Palanisamy

Kalyana-Sundaram

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Recently, reciprocal RNA chimera involving YPEL5 and PPP1CB was identifi ed by transcriptome sequencing, and no corresponding rearrangement at the DNA level was found ( 4 ). In addition, we reported cis -splicing of adjacent genes as another mechanism to generate SLC45A3-ELK4 chimera involving neighboring genes transcribing in the same direction ( 5 ).…”

Section: Introductionmentioning

confidence: 89%

A Chimeric RNA Characteristic of Rhabdomyosarcoma in Normal Myogenesis Process

et al. 2013

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Gene fusions and their chimeric products are common features of neoplasia. Given that many cancers arise by the dysregulated recapitulation of processes in normal development, we hypothesized that comparable chimeric gene products may exist in normal cells. Here, we show that a chimeric RNA, PAX3-FOXO1 , identical to that found in alveolar rhabdomyosarcoma, is transiently present in cells undergoing differentiation from pluripotent cells into skeletal muscle. Unlike cells of rhabdomyosarcoma, these cells do not seem to harbor the t(2;13) chromosomal translocation. Importantly, both PAX3-FOXO1 RNA and protein could be detected in the samples of normal fetal muscle. Overexpression of the chimera led to continuous expression of MYOD and MYOG-two myogenic markers that are overexpressed in rhabdomyosarcoma cells. Our results are consistent with a developmental role of a specifi c chimeric RNA generated in normal cells without the corresponding chromosomal rearrangement at the DNA level seen in neoplastic cells presumably of the same lineage. SIGNIFICANCE:A chimeric fusion RNA, PAX3-FOXO1 , associated with alveolar rhabdomyosarcoma, is also present in normal non-cancer cells and tissues. Its transient expression nature and the absence of t(2;13) chromosomal translocation are consistent with a posttranscriptional mechanism. When constantly expressed, PAX3-FOXO1 interfered with the muscle differentiation process, which presumably contributes to tumorigenesis.

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“…Identification of the characteristics of these regions will be very helpful in addressing the question as to whether or not there are common mechanisms of full-length ETV1 overexpression. In a small percentage of prostate tumors, the ETS gene ELK4 is overexpressed due to cis-splicing of the flanking SLC45A3 gene (Rickman et al 2009, Zhang et al 2012. The finding that the expression of ETS transcription factors is mutually exclusive in clinical prostate cancers might not necessarily indicate a similar function.…”

Section: Functions Of Ets Transcription Factorsmentioning

confidence: 99%

ETS fusion genes in prostate cancer

Tandefelt¹,

Boormans²,

Hermans³

et al. 2014

Endocrine-Related Cancer

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Prostate cancer is very common in elderly men in developed countries. Unravelling the molecular and biological processes that contribute to tumor development and progressive growth, including its heterogeneity, is a challenging task. The fusion of the genes ERG and TMPRSS2 is the most frequent genomic alteration in prostate cancer. ERG is an oncogene that encodes a member of the family of ETS transcription factors. At lower frequency, other members of this gene family are also rearranged and overexpressed in prostate cancer. TMPRSS2 is an androgen-regulated gene that is preferentially expressed in the prostate. Most of the less frequent ETS fusion partners are also androgen-regulated and prostatespecific. During the last few years, novel concepts of the process of gene fusion have emerged, and initial experimental results explaining the function of the ETS genes ERG and ETV1 in prostate cancer have been published. In this review, we focus on the most relevant ETS gene fusions and summarize the current knowledge of the role of ETS transcription factors in prostate cancer. Finally, we discuss the clinical relevance of TMRPSS2-ERG and other ETS gene fusions in prostate cancer.

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Chimeric Transcript Generated by cis-Splicing of Adjacent Genes Regulates Prostate Cancer Cell Proliferation

Cited by 145 publications

References 28 publications

Recurrent reciprocal RNA chimera involving YPEL5 and PPP1CB in chronic lymphocytic leukemia

Recurrent reciprocal RNA chimera involving YPEL5 and PPP1CB in chronic lymphocytic leukemia

A Chimeric RNA Characteristic of Rhabdomyosarcoma in Normal Myogenesis Process

ETS fusion genes in prostate cancer

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