Novel canine isocitrate dehydrogenase 1 mutation Y208C attenuates dimerization ability

Kawakami,Shota; Michishita,Masaki; Sakaue,Motoharu; Morimatsu,Masami; Uemura,Mitsuki; Kashiwagi,Nobuaki; Maeda,Marika; Machida,Yukino; Azakami,Daigo; Egusa,Ai S.; Onozawa,Eri; Ishioka,Katsumi; Watanabe,Masami; Tanaka,Yoshikazu; Omi,Toshinori; Ochiai,Kazuhiko

doi:10.3892/ol.2020.12214

Novel canine isocitrate dehydrogenase 1 mutation Y208C attenuates dimerization ability

Authors:
- Shota Kawakami
- Masaki Michishita
- Motoharu Sakaue
- Masami Morimatsu
- Mitsuki Uemura
- Nobuaki Kashiwagi
- Marika Maeda
- Yukino Machida
- Daigo Azakami
- Ai S. Egusa
- Eri Onozawa
- Katsumi Ishioka
- Masami Watanabe
- Yoshikazu Tanaka
- Toshinori Omi
- Kazuhiko Ochiai
View Affiliations

Affiliations: School of Veterinary Nursing and Technology, Faculty of Veterinary Science, Musashino, Tokyo 180‑8602, Japan, Laboratory of Veterinary Pathology, School of Veterinary Science, Musashino, Tokyo 180‑8602, Japan, Laboratory of Anatomy II, Department of Veterinary Medicine, School of Veterinary Medicine, Azabu University, Sagamihara, Kanagawa 252‑5201, Japan, Laboratory of Animal Science and Medicine, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060‑0818, Japan, Laboratory of Veterinary Hygiene, School of Veterinary Science, Nippon Veterinary and Life Science University, Musashino, Tokyo 180‑8602, Japan, Laboratory of Clinical Oncology, Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo 183‑8538, Japan, Department of Applied Life Science, Faculty of Food Science, Nippon Veterinary and Life Science University, Musashino, Tokyo 180-8602, Japan, Department of Urology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700‑8558, Japan, Research Center for Animal Life Science, Nippon Veterinary and Life Science University, Musashino, Tokyo 180‑8602, Japan
Published online on: October 11, 2020 https://doi.org/10.3892/ol.2020.12214
Article Number: 351
Copyright: © Kawakami et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Isocitrate dehydrogenase 1 (IDH1) mutations are common in gliomas, acute myeloid leukemia, and chondrosarcoma. The mutation ‘hotspot’ is a single arginine residue, R132. The R132H mutant of IDH1 produces the 2‑hydroxyglutarate (2‑HG) carcinogen from α‑ketoglutarate (α‑KG). The reduction of α‑KG induces the accumulation of hypoxia‑inducible factor‑1α subunit (HIF‑1α) in the cytosol, which is a predisposing factor for carcinogenesis. R132H is the most common IDH1 mutation in humans, but mutations at the R132 residue can also occur in tumor tissues of dogs. The current study reported the discovery of a novel Tyr208Cys (Y208C) mutation in canine IDH1 (cIDH1), which was isolated from 2 of 45 canine chondrosarcoma cases. As the genomic DNA isolated from chondrosarcoma tissue was mutated, but that isolated from blood was not, Y208C mutations were considered to be spontaneous somatic mutations. The isocitrate dehydrogenase activity of the Y208C mutant was attenuated compared with that of wild‑type (WT) cIDH1, but the attenuation of Y208C was less intense than that of the R132H mutation. The induction of HIF‑1α response element activity and cell retention of HIF‑1α were not increased by Y208C overexpression. In silico and cell biological analysis of IDH1 dimerization revealed that the Y208C mutation, but not the R132H mutation, attenuated binding activity with WT cIDH1. These data suggested that the attenuation of dimerization by the Y208C mutation may cause tumorigenesis through different mechanisms other than via 2‑HG production by the IDH1 R132 mutation.

View Figures

View References

1	Sahm F, Reuss D, Koelsche C, Capper D, Schittenhelm J, Heim S, Jones DT, Pfister SM, Herold-Mende C, Wick W, et al: Farewell to oligoastrocytoma: In situ molecular genetics favor classification as either oligodendroglioma or astrocytoma. Acta Neuropathol. 128:551–559. 2014. View Article : Google Scholar : PubMed/NCBI
2	Lapointe S, Perry A and Butowski NA: Primary brain tumours in adults. Lancet. 392:432–446. 2018. View Article : Google Scholar : PubMed/NCBI
3	Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, et al: An integrated genomic analysis of human glioblastoma multiforme. Science. 321:1807–1812. 2008. View Article : Google Scholar : PubMed/NCBI
4	Reitman ZJ and Yan H: Isocitrate dehydrogenase 1 and 2 mutations in cancer: Alterations at a crossroads of cellular metabolism. J Natl Cancer Inst. 102:932–941. 2010. View Article : Google Scholar : PubMed/NCBI
5	Bleeker FE, Lamba S, Rodolfo M, Scarpa A, Leenstra S, Vandertop WP and Bardelli A: Mutational profiling of cancer candidate genes in glioblastoma, melanoma and pancreatic carcinoma reveals a snapshot of their genomic landscapes. Hum Mutat. 30:E451–E459. 2009. View Article : Google Scholar : PubMed/NCBI
6	Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, et al: IDH1 and IDH2 mutations in gliomas. N Engl J Med. 360:765–773. 2009. View Article : Google Scholar : PubMed/NCBI
7	Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K, Koboldt DC, Fulton RS, Delehaunty KD, McGrath SD, et al: Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med. 361:1058–1066. 2009. View Article : Google Scholar : PubMed/NCBI
8	Lugowska I, Teterycz P, Mikula M, Kulecka M, Kluska A, Balabas A, Piatkowska M, Wagrodzki M, Pienkowski A, Rutkowski P and Ostrowski J: IDH1/2 mutations predict shorter survival in chondrosarcoma. J Cancer. 9:998–1005. 2018. View Article : Google Scholar : PubMed/NCBI
9	Waitkus MS, Diplas BH and Yan H: Biological role and therapeutic potential of IDH mutations in cancer. Cancer Cell. 34:186–195. 2018. View Article : Google Scholar : PubMed/NCBI
10	Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC, et al: Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 462:739–744. 2009. View Article : Google Scholar : PubMed/NCBI
11	Gross S, Cairns RA, Minden MD, Driggers EM, Bittinger MA, Jang HG, Sasaki M, Jin S, Schenkein DP, Su SM, et al: Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J Exp Med. 207:339–344. 2010. View Article : Google Scholar : PubMed/NCBI
12	Schnittger S, Haferlach C, Ulke M, Alpermann T, Kern W and Haferlach T: IDH1 mutations are detected in 6.6% of 1414 AML patients and are associated with intermediate risk karyotype and unfavorable prognosis in adults younger than 60 years and unmutated NPM1 status. Blood. 116:5486–5496. 2010. View Article : Google Scholar : PubMed/NCBI
13	Wajner M, Latini A, Wyse AT and Dutra-Filho CS: The role of oxidative damage in the neuropathology of organic acidurias: insights from animal studies. J Inherit Metab Dis. 27:427–448. 2004. View Article : Google Scholar : PubMed/NCBI
14	Zhao S, Lin Y, Xu W, Jiang W, Zha Z, Wang P, Yu W, Li Z, Gong L, Peng Y, et al: Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science. 324:261–265. 2009. View Article : Google Scholar : PubMed/NCBI
15	Calvert AE, Chalastanis A, Wu Y, Hurley LA, Kouri FM, Bi Y, Kachman M, May JL, Bartom E, Hua Y, et al: Cancer-associated IDH1 promotes growth and resistance to targeted therapies in the absence of mutation. Cell Rep. 19:1858–1873. 2017. View Article : Google Scholar : PubMed/NCBI
16	Wahl DR, Dresser J, Wilder-Romans K, Parsels JD, Zhao SG, Davis M, Zhao L, Kachman M, Wernisch S, Burant CF, et al: Glioblastoma therapy can be augmented by targeting IDH1-mediated NADPH biosynthesis. Cancer Res. 77:960–970. 2017. View Article : Google Scholar : PubMed/NCBI
17	Zarei M, Lal S, Parker SJ, Nevler A, Vaziri-Gohar A, Dukleska K, Mambelli-Lisboa NC, Moffat C, Blanco FF, Chand SN, et al: Posttranscriptional upregulation of IDH1 by HuR establishes a powerful survival phenotype in pancreatic cancer cells. Cancer Res. 77:4460–4471. 2017. View Article : Google Scholar : PubMed/NCBI
18	Dobson JM, Samuel S, Milstein H, Rogers K and Wood JL: Canine neoplasia in the UK: Estimates of incidence rates from a population of insured dogs. J Small Anim Pract. 43:240–246. 2002. View Article : Google Scholar : PubMed/NCBI
19	Reitman ZJ, Olby NJ, Mariani CL, Thomas R, Breen M, Bigner DD, McLendon RE and Yan H: IDH1 and IDH2 hotspot mutations are not found in canine glioma. Int J Cancer. 127:245–246. 2010. View Article : Google Scholar : PubMed/NCBI
20	Kawakami S, Ochiai K, Azakami D, Kato Y, Michishita M, Morimatsu M, Ishiguro-Oonuma T, Onozawa E, Watanabe M and Omi T: R132 mutations in canine isocitrate dehydrogenase 1 (IDH1) lead to functional changes. Vet Res Commun. 42:49–56. 2018. View Article : Google Scholar : PubMed/NCBI
21	Kaneko MK, Tian W, Takano S, Suzuki H, Sawa Y, Hozumi Y, Goto K, Yamazaki K, Kitanaka C and Kato Y: Establishment of a novel monoclonal antibody SMab-1 specific for IDH1-R132S mutation. Biochem Biophys Res Commun. 406:608–613. 2011. View Article : Google Scholar : PubMed/NCBI
22	Kato Y: Specific monoclonal antibodies against IDH1/2 mutations as diagnostic tools for gliomas. Brain Tumor Pathol. 32:3–11. 2015. View Article : Google Scholar : PubMed/NCBI
23	Amin SB, Anderson KJ, Boudreau CE, Martinez-Ledesma E, Kocakavuk E, Johnson KC, Barthel FP, Varn FS, Kassab C, Ling X, et al: Comparative molecular life history of spontaneous canine and human gliomas. Cancer Cell. 37:243–257.e7. 2020. View Article : Google Scholar : PubMed/NCBI
24	Misdorp W, Else RW, Hellmen E and Lipscomb TP: Histological classification of mammary tumors of the dog and the cat. World Health Organization International Histological Classification of Tumors of Domestic Animals. Schulman FY: 7. 2nd Series. Armed Forces Institute of Pathology; Washington, DC: pp. 581999
25	Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC and Ferrin TE: UCSF Chimera-a visualization system for exploratory research and analysis. J Comput Chem. 25:1605–1612. 2004. View Article : Google Scholar : PubMed/NCBI
26	Jalil JE, Perez A, Ocaranza MP, Bargetto J, Galaz A and Lavandero S: Increased aortic NADPH oxidase activity in rats with genetically high angiotensin-converting enzyme levels. Hypertension. 46:1362–1367. 2005. View Article : Google Scholar : PubMed/NCBI
27	Emerling BM, Platanias LC, Black E, Nebreda AR, Davis RJ and Chandel NS: Mitochondrial reactive oxygen species activation of p38 mitogen-activated protein kinase is required for hypoxia signaling. Mol Cell Biol. 25:4853–4862. 2005. View Article : Google Scholar : PubMed/NCBI
28	Preusser M, Wohrer A, Stary S, Hoftberger R, Streubel B and Hainfellner JA: Value and limitations of immunohistochemistry and gene sequencing for detection of the IDH1-R132H mutation in diffuse glioma biopsy specimens. J Neuropathol Exp Neurol. 70:715–723. 2011. View Article : Google Scholar : PubMed/NCBI
29	Ashraf S, Noguera NI, Di Giandomenico J, Zaza S, Hasan SK and Lo-Coco F: Rapid detection of IDH2 (R140Q and R172K) mutations in acute myeloid leukemia. Ann Hematol. 92:1319–1323. 2013. View Article : Google Scholar : PubMed/NCBI
30	Catteau A, Girardi H, Monville F, Poggionovo C, Carpentier S, Frayssinet V, Voss J, Jenkins R, Boisselier B, Mokhtari K, et al: A new sensitive PCR assay for one-step detection of 12 IDH1/2 mutations in glioma. Acta Neuropathol Commun. 2:582014. View Article : Google Scholar : PubMed/NCBI
31	Truve K, Dickinson P, Xiong A, York D, Jayashankar K, Pielberg G, Koltookian M, Muren E, Fuxelius HH, Weishaupt H, et al: Utilizing the dog genome in the search for novel candidate genes involved in glioma development-genome wide association mapping followed by targeted massive parallel sequencing identifies a strongly associated locus. PLoS Genet. 12:e10060002016. View Article : Google Scholar : PubMed/NCBI
32	Tate JG, Bamford S, Jubb HC, Sondka Z, Beare DM, Bindal N, Boutselakis H, Cole CG, Creatore C, Dawson E, et al: COSMIC: The catalogue of somatic mutations in cancer. Nucleic Acids Res. 47:D941–D947. 2019. View Article : Google Scholar : PubMed/NCBI
33	Huang LE: Friend or foe-IDH1 mutations in glioma 10 years on. Carcinogenesis. 40:1299–1307. 2019. View Article : Google Scholar : PubMed/NCBI
34	Koyasu S, Shimizu Y, Morinibu A, Saga T, Nakamoto Y, Togashi K and Harada H: Increased ¹⁴C-acetate accumulation in IDH-mutated human glioblastoma: Implications for detecting IDH-mutated glioblastoma with ¹¹C-acetate PET imaging. J Neuro Oncol. 145:441–447. 2019. View Article : Google Scholar
35	Zhao S and Guan KL: IDH1 mutant structures reveal a mechanism of dominant inhibition. Cell Res. 20:1279–1281. 2010. View Article : Google Scholar : PubMed/NCBI
36	Vinekar R, Verma C and Ghosh I: Functional relevance of dynamic properties of Dimeric NADP-dependent isocitrate dehydrogenases. BMC Bioinformatics. 13 (Suppl 17):S22012. View Article : Google Scholar : PubMed/NCBI