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Through Transcription of PHOSPHO2& Overexpression of KLHL23 protein from read-through transcription of PHOSPHO2-KLHL23 in gastric cancer increases cell proliferation Eun-Seok Choi1,2, Hanna Lee1, Chang-Hun Lee3 and Sung-Ho Goh1 1 Precision Medicine Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi-do, Korea 2 Department of Environmental Medical Biology, Institute of Tropical Medicine, Yonsei University College of Medicine, Seoul, Korea 3 Cancer Cell and Molecular Biology Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi-do, Korea Keywords Gene fusion, as a prototypical pathognomonic mutation, contributes to gastric cancer; PHOPHO2-KLHL23; read- genome complexity, and the cis-transcription-induced gene fusions gener- through transcription ated by read-through transcription of adjacent genes have been found to be important for tumor development. We screened read-through transcrip- Correspondence S.-H. Goh, Precision Medicine Branch, tion events from stomach adenocarcinoma RNA-seq data and selected Research Institute, National Cancer Center, three candidates PHOSPHO2-KLHL23, RPL17-C18orf32, and PRR5- 323 Ilsanro, Goyang, Gyeonggi-do 10408, ARHGAP8, to assess their biological role in gastric cancer. The expression Korea of all three read-through fusion transcripts was confirmed in gastric cancer Tel: +82 31 920 2477 cell lines and paired normal/tumor gastric cancer tissues by real-time quan- E-mail: [email protected] titative reverse transcription polymerase chain reaction and their expression was found to be significantly higher in the tumor (P < 0.05; n = 75). The (Received 21 June 2016, revised 20 September 2016, accepted 28 September correlation between the expression level and clinicopathological informa- 2016) tion was statistically analyzed. The level of the PHOSPHO2-KLHL23 read-through fusion transcript correlated with the Lauren classification and doi:10.1002/2211-5463.12136 was significantly associated with the presence of perineural invasion. Over- expression of KLHL23 from PHOSPHO2-KLHL23 read-through tran- script led to a significant increase in cell proliferation and resistance to anticancer drug treatment. Silencing of KLHL23 expression decreased cyclin D1 levels. The expression of KLHL23 from prevalent read-through transcripts of PHOSPHO2-KLHL23 in gastric cancer may undermine the efficacy of anticancer drug treatment. Genetic alterations are tightly associated with the transcriptome. Gene fusion events originate predomi- development of neoplasia. The types and patterns of nantly from chromosomal rearrangements, which are such mutations are highly variable and heterogeneous important cancer-associated somatic alterations [2]. within a single entity as well as between different tumor One of the representative examples is BCR-ABL1, first categories. Gene fusions are a prototypical example of reported in chronic myeloid leukemia. Identification pathognomonic mutations in tumorigenesis, and the and characterization of this fusion led to discoveries of detection and characterization of gene fusion events is novel therapeutics for tyrosine kinase inhibition, such of considerable importance for clinical purposes and as dasatinib and imatinib (Gleevec) [3]. for understanding tumorigenesis [1]. Recent advances In addition to the fusion events generated by chro- in sequencing technology have enabled a comprehen- mosomal rearrangements, gene fusion by read-through sive detection of rearrangements in cancer genome and transcription, also known as transcription-induced Abbreviations HDF, human dermal fibroblast; SRA, sequence read archives. FEBS Open Bio 6 (2016) 1155–1164 ª 2016 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. 1155 This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. KLHL23 from PHOSPHO2-KLHL23 read-through transcription E.-S. Choi et al. gene fusion, occurs when two of adjacent genes on the [19]. The function of PHOSPHO2 (Phosphatase, cis-strand are spliced together [4]. The existence of Orphan 2) has been attributed to the vitamin B6 path- such chimeric structured transcripts has been sporadi- way, but not to any tumorigenic phenomenon [20]. cally reported before the systematic survey of human In this study, we screened the fusion gene databases transcriptome by the ENCODE project [5,6]. In these and selected read-through transcription-induced chi- studies, many candidate expressed sequence tags were meras detected in gastric tissues. Among those, the found to cross the border of individual genes and span read-through transcripts that included proteins whose both genes in the pair. The frequency of the read- biological properties could be relevant to oncogenic through transcription events was estimated to be only activity were validated in tissue samples from patients 4–6% of genes in the human genome [7]. with gastric cancer and analyzed further. The prevailing hypothesis of the read-through tran- scription mechanism is transcriptional ‘leakage’ that occurs when transcription of polymerizing RNA is not Materials and methods terminated at the upstream gene and proceeds to the adjacent downstream gene on a single-strand transcript Database search of read-through transcription [5]. Epigenetic inactivation by promoter methylation candidates or deletion of the poly(A) transcription termination For the screening of read-through fusion transcripts from signal, which prevents proceeding of RNA polymerase gastric cancer tissues, totally 42 sequence read archives II to the next gene, also results in read-through tran- (SRA) files (raw data files) for RNA-seq were selected for scription in cancer [8,9]. When a read-through tran- 30 gastric tissues and 12 stomach cancer cell lines and script is spliced into a gene fusion, it follows several downloaded from NCBI SRA archive and European intergenic splicing patterns, and most of them (44%) Nucleotide Archives of EMBL-EBI. These data were ana- occur between two exons, exon (n À 1) (one before the lyzed to generate fusion candidate using fusion detection last) from the proximal gene and the exon 2 of the dis- software, including TOPHAT FUSION [21] and FUSIONQ,[22] tal gene [10]. Therefore, the fusion transcripts can pass but excluded false-positive detection with low complexity. the termination of translation, when they are engaged The Human genome build hg.19 was used as a reference in the ribosome machinery. genome for this analysis. We also searched fusion gene can- These kinds of variations in the transcriptome are didates from COSMIC [23] and ConjoinG databases the source of generating diversity of proteins translated (http://metasystems.riken.jp/conjoing/index). from a finite number of genes in the genome, and a mechanism contributing to the evolution of protein Cell lines and fresh human tissue samples complexities. In certain cases, read-through transcrip- tion is translated into functional protein products that In this study, we used AGS, MKN-28, KATO-III, and could contribute to the progression of diseases, espe- human dermal fibroblast (HDF) cell lines obtained from American Type Culture Collection (Manassas, VA, USA), cially to tumor development. For example, CUL3- and SNU-638 and SNU-216 cell lines from Korea Cell Line KLHL7 attenuation is related to a retinitis pigmentosa Bank (Seoul, Korea). All the cells were cultured with desig- causative mutation [11], SLC45A3-ELK4 expression nated media (Cellgro; Corning, Manassas, VA, USA) sup- level correlates with prostate cancer progression [12], plemented with 10% FBS serum (Cellgro; Corning) and 19 YPEL5-PPP1CB is involved in the development of Penicillin Streptomycin (Invitrogen, Carlsbad, CA, USA) at chronic lymphocytic leukemia [13]. Aberrant read- 37 °C containing 5% CO2. through transcription has been also reported to con- Fresh human stomach tissues were obtained from tribute to the formation of solid tumors in colorectal patients who agree the informed consent approved by insti- cancer [14,15], renal cell carcinoma [16], bladder cancer tutional review board of National Cancer Center of Korea [17], and breast cancer [18]. However, there have been (NCCNCS13732; Table 1). Dissected tissues were stored in no reports about the read-through transcription pro- RNA later solution (Qiagen, Hilden, Germany) for total files in gastric cancer. RNA extraction or liquid nitrogen for protein extraction. The biological functions of the read-through fusion gene components analyzed in this study have not been RT-PCR and quantitative RT-PCR characterized with respect to their possible tumorigenic role. For example, the expression of KLHL23 (Kelch- Total RNA was extracted using Trizol reagent (Invitrogen) Like Family Member 23) during tumorigenesis in can- according to the manufacturer’s protocol and purified with cer has not been previously evaluated, although its RNeasy column with RNase-free DNaseI treatment (Qia- association with cone-rod dystrophy has been reported gen). We used one microgram of total RNA to synthesize 1156 FEBS Open Bio 6 (2016) 1155–1164 ª 2016 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. E.-S. Choi et al. KLHL23 from PHOSPHO2-KLHL23 read-through transcription Table 1. Clinicopathological information of gastric cancer patients Assessments of read-through fusion transcript for mRNA expression-level assessment between tumor and normal effect on tumorigenesis tissues (n = 75). PHOSPHO2-KLHL23 expression was silenced in AGS gas- n tric
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