Characterization of regulatory sequences in alternative promoters of hypermethylated genes associated with tumor resistance to cisplatin

Ibrahim‑Alobaide,Mohammed   A.; Abdelsalam,Abdelsalam   G.; Alobydi,Hytham; Rasul,Kakil   Ibrahim; Zhang,Ruiwen; Srivenugopal,Kalkunte   S.

doi:10.3892/mco.2014.468

Characterization of regulatory sequences in alternative promoters of hypermethylated genes associated with tumor resistance to cisplatin

Authors:
- Mohammed A. Ibrahim‑Alobaide
- Abdelsalam G. Abdelsalam
- Hytham Alobydi
- Kakil Ibrahim Rasul
- Ruiwen Zhang
- Kalkunte S. Srivenugopal
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Affiliations: Department of Biomedical Sciences and Cancer Biology Research Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA, Department of Mathematics, Statistics and Physics, College of Arts and Sciences, Qatar University, Doha, Qatar, Biomedica, LLC, Sterling Heights, MI 48310, USA, Weill Cornell Medical College and Hamad Medical Corporation, Doha, Qatar, Department of Pharmaceutical Sciences and Cancer Biology Research Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA
Published online on: November 27, 2014 https://doi.org/10.3892/mco.2014.468
Pages: 408-414

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Abstract

The development of cisplatin resistance in human cancers is controlled by multiple genes and leads to therapeutic failure. Hypermethylation of specific gene promoters is a key event in clinical resistance to cisplatin. Although the usage of multiple promoters is frequent in the transcription of human genes, the role of alternative promoters and their regulatory sequences have not yet been investigated in cisplatin resistance genes. In a new approach, we hypothesized that human cancers exploit the specific transcription factor‑binding sites (TFBS) and CpG islands (CGIs) located in the alternative promoters of certain genes to acquire platinum drug resistance. To provide a useful resource of regulatory elements associated with cisplatin resistance, we investigated the TFBS and CGIs in 48 alternative promoters of 14 hypermethylated cisplatin resistance genes previously reported. CGIs prone to methylation were identified in 28 alternative promoters of 11 hypermethylated genes. The majority of alternative promoters harboring CGIs (93%) were clustered in one phylogenetic subclass, whereas the ones lacking CGIs were distributed in two unrelated subclasses. Regulatory sequences, initiator and TATA‑532 prevailed over TATA‑8 and were found in all the promoters. B recognition element (BRE) sequences were present only in alternative promoters harboring CGIs, but CCAAT and TAACC were found in both types of alternative promoters, whereas downstream promoter element sequences were significantly less frequent. Therefore, it was hypothesized that BRE and CGI sequences co‑localized in alternative promoters of cisplatin resistance genes may be used to design molecular markers for drug resistance. A more extensive knowledge of alternative promoters and their regulatory elements in clinical resistance to cisplatin is likely to usher novel avenues for sensitizing human cancers to treatment.

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1	Siddik ZH: Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene. 22:7265–7279. 2003. View Article : Google Scholar : PubMed/NCBI
2	Kelland L: The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer. 7:573–584. 2007. View Article : Google Scholar : PubMed/NCBI
3	Rabik CA and Dolan ME: Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treat Rev. 33:9–23. 2007. View Article : Google Scholar : PubMed/NCBI
4	Akervall J, Guo X, Qian CN, et al: Genetic and expression profiles of squamous cell carcinoma of the head and neck correlate with cisplatin sensitivity and resistance in cell lines and patients. Clin Cancer Res. 10:8204–8213. 2004. View Article : Google Scholar : PubMed/NCBI
5	Tsunoda T, Koga H, Yokomizo A, et al: Inositol 1, 4, 5-trisphosphate (IP3) receptor type1 (IP3R1) modulates the acquisition of cisplatin resistance in bladder cancer cell lines. Oncogene. 24:1396–1402. 2005. View Article : Google Scholar : PubMed/NCBI
6	Zeller C, Dai W, Steele NL, et al: Candidate DNA methylation drivers of acquired cisplatin resistance in ovarian cancer identified by methylome and expression profiling. Oncogene. 31:4567–4576. 2012. View Article : Google Scholar : PubMed/NCBI
7	Zhang YW, Zheng Y, Wang JZ, et al: Integrated analysis of DNA methylation and mRNA expression profiling reveals candidate genes associated with cisplatin resistance in non-small cell lung cancer. Epigenetics. 9:896–909. 2014. View Article : Google Scholar : PubMed/NCBI
8	Guo R, Wu G, Li H, et al: Promoter methylation profiles between human lung adenocarcinoma multidrug resistant A549/cisplatin (A549/DDP) cells and its progenitor A549 cells. Biol Pharm Bull. 36:1310–1316. 2013. View Article : Google Scholar : PubMed/NCBI
9	Chang X, Monitto CL, Demokan S, et al: Identification of hypermethylated genes associated with cisplatin resistance in human cancers. Cancer Res. 70:2870–2879. 2010. View Article : Google Scholar : PubMed/NCBI
10	Batut P, Dobin A, Plessy C, Carninci P and Gingeras TR: High-fidelity promoter profiling reveals widespread alternative promoter usage and transposon-driven developmental gene expression. Genome Res. 23:169–180. 2013. View Article : Google Scholar : PubMed/NCBI
11	Davuluri RV, Suzuki Y, Sugano S, Plass C and Huang TH: The functional consequences of alternative promoter use in mammalian genomes. Trends Genet. 24:167–177. 2008. View Article : Google Scholar : PubMed/NCBI
12	Ayoubi TA and Van De Ven WJ: Regulation of gene expression by alternative promoters. FASEB J. 10:453–460. 1996.PubMed/NCBI
13	Jacox E, Gotea V, Ovcharenko I and Elnitski L: Tissue-specific and ubiquitous expression patterns from alternative promoters of human genes. PLoS One. 5:e122742010. View Article : Google Scholar : PubMed/NCBI
14	Schibler U and Sierra F: Alternative promoters in developmental gene expression. Annu Rev Genet. 21:237–257. 1987. View Article : Google Scholar : PubMed/NCBI
15	Liu H, Zhang Y, Li S, Yan Y and Li Y: Dynamic regulation of glutamate decarboxylase 67 gene expression by alternative promoters and splicing during rat testis maturation. Mol Biol Rep. 37:3111–3119. 2010. View Article : Google Scholar : PubMed/NCBI
16	Xin D, Hu L and Kong X: Alternative promoters influence alternative splicing at the genomic level. PLoS One. 3:e23772008. View Article : Google Scholar : PubMed/NCBI
17	Elso C, Lu X, Weisner PA, Thompson HL, et al: A reciprocal translocation dissects roles of Pa×6 alternative promoters and upstream regulatory elements in the development of pancreas, brain, and eye. Genesis. 51:630–646. 2013.PubMed/NCBI
18	Smith RP, Lam ET, Markova S, Yee SW and Ahituv N: Pharmacogene regulatory elements: from discovery to applications. Genome Med. 4:452012. View Article : Google Scholar : PubMed/NCBI
19	Cusanovich DA, Pavlovic B, Pritchard JK and Gilad Y: The functional consequences of variation in transcription factor binding. PLoS Genet. 10:e10042262014. View Article : Google Scholar : PubMed/NCBI
20	Yang C, Bolotin E, Jiang T, Sladek FM and Martinez E: Prevalence of the initiator over the TATA box in human and yeast genes and identification of DNA motifs enriched in human TATA-less core promoters. Gene. 389:52–65. 2007. View Article : Google Scholar : PubMed/NCBI
21	Hsu PC, Chao CC, Yang CY, et al: Diverse Hap43-independent functions of the Candida albicans CCAAT-binding complex. Eukaryot Cell. 12:804–815. 2013. View Article : Google Scholar : PubMed/NCBI
22	Gardiner-Garden M and Frommer M: CpG islands in vertebrate genomes. J Mol Biol. 196:261–282. 1987. View Article : Google Scholar : PubMed/NCBI
23	Han L and Zhao Z: CpG islands or CpG clusters: how to identify functional GC-rich regions in a genome? BMC Bioinformatics. 10:652009. View Article : Google Scholar : PubMed/NCBI
24	Zhao Z and Han L: CpG islands: algorithms and applications in methylation studies. Biochem Biophys Res Commun. 382:643–645. 2009. View Article : Google Scholar : PubMed/NCBI
25	Hackenberg M, Barturen G, Carpena P, Luque-Escamilla PL, Previti C and Oliver JL: Prediction of CpG-island function: CpG clustering vs. sliding-window methods. BMC Genomics. 11:3272010. View Article : Google Scholar : PubMed/NCBI
26	FANTOM Consortium the RIKEN PMI and CLST (DGT)Forrest AR, Kawaji H, et al: A promoter-level mammalian expression atlas. Nature. 507:462–470. 2014. View Article : Google Scholar : PubMed/NCBI
27	Ben-Tabou de-Leon S and Davidson EH: Gene regulation: gene control network in development. Annu Rev Biophys Biomol Struct. 36:191–212. 2007. View Article : Google Scholar : PubMed/NCBI
28	Jeziorska DM, Jordan KW and Vance KW: A systems biology approach to understanding cis-regulatory module function. Semin Cell Dev Biol. 20:856–862. 2009. View Article : Google Scholar : PubMed/NCBI
29	Cameron RA and Davidson EH: Flexibility of transcription factor target site position in conserved cis-regulatory modules. Dev Biol. 336:122–135. 2009. View Article : Google Scholar : PubMed/NCBI
30	Vavouri T and Elgar G: Prediction of cis-regulatory elements using binding site matrices - the successes, the failures and the reasons for both. Curr Opin Genet Dev. 15:395–402. 2005. View Article : Google Scholar : PubMed/NCBI
31	Maston GA, Evans SK and Green MR: Transcriptional regulatory elements in the human genome. Annu Rev Genomics Hum Genet. 7:29–59. 2006. View Article : Google Scholar : PubMed/NCBI
32	Maston GA, Zhu LJ, Chamberlain L, Lin L, Fang M and Green MR: Non-canonical TAF complexes regulate active promoters in human embryonic stem cells. Elife. 1:e000682012. View Article : Google Scholar : PubMed/NCBI
33	Jaksik R and Rzeszowska-Wolny J: The distribution of GC nucleotides and regulatory sequence motifs in genes and their adjacent sequences. Gene. 492:375–381. 2012. View Article : Google Scholar : PubMed/NCBI
34	Martinez E: Core promoter-selective coregulators of transcription by RNA polymerase II. Transcription. 3:295–299. 2012. View Article : Google Scholar : PubMed/NCBI
35	Gross P and Oelgeschläger T: Core promoter-selective RNA polymerase II transcription. Biochem Soc Symp. 73:225–236. 2006.PubMed/NCBI
36	Bucher P: Weight matrix descriptions of four eukaryotic RNA polymerase II promoter elements derived from 502 unrelated promoter sequences. J Mol Biol. 212:563–578. 1990. View Article : Google Scholar : PubMed/NCBI
37	Camacho-Arroyo I, Hansberg-Pastor V and Rodríguez-Dorantes M: DNA methylation analysis of steroid hormone receptor genes. Methods Mol Biol. 1165:89–98. 2014.PubMed/NCBI
38	Cocozza S, Scala G, Miele G, Castaldo I and Monticelli A: A distinct group of CpG islands shows differential DNA methylation between replicas of the same cell line in vitro. BMC Genomics. 14:6922013. View Article : Google Scholar : PubMed/NCBI
39	Tanaka T, Bai T, Toujima S, et al: Demethylation restores SN38 sensitivity in cells with acquired resistance to SN38 derived from human cervical squamous cancer cells. Oncol Rep. 27:1292–1298. 2012.PubMed/NCBI
40	Yang D and Okamoto K: Structural insights into G-quadruplexes: towards new anticancer drugs. Future Med Chem. 2:619–646. 2010. View Article : Google Scholar : PubMed/NCBI
41	Chen Y and Yang D: Sequence, stability, and structure of G-quadruplexes and their interactions with drugs. Curr Protoc Nucleic Acid Chem. 17:Unit17.52012.PubMed/NCBI
42	Hudson JS, Brooks SC and Graves DE: Interactions of actinomycin D with human telomeric G-quadruplex DNA. Biochemistry. 48:4440–4447. 2009. View Article : Google Scholar : PubMed/NCBI
43	Meng H, Wang J, Xiong Z, Xu F, Zhao G and Wang Y: Quantitative design of regulatory elements based on high-precision strength prediction using artificial neural network. PLoS One. 8:e602882013. View Article : Google Scholar : PubMed/NCBI
44	Brewster RC, Jones DL and Phillips R: Tuning promoter strength through RNA polymerase binding site design in Escherichia coli. PLoS Comput Biol. 8:e10028112012. View Article : Google Scholar : PubMed/NCBI
45	Hosseinpour B, Bakhtiarizadeh MR, Khosravi P and Ebrahimie E: Predicting distinct organization of transcription factor binding sites on the promoter regions: a new genome-based approach to expand human embryonic stem cell regulatory network. Gene. 531:212–219. 2013. View Article : Google Scholar : PubMed/NCBI
46	Lai FJ, Chiu CC, Yang TH, Huang YM and Wu WS: Identifying functional transcription factor binding sites in yeast by considering their positional preference in the promoters. PLoS One. 8:e837912013. View Article : Google Scholar : PubMed/NCBI