Abstract
Allelic deletions on human chromosome 12q24 are frequently reported in a variety of malignant neoplasms, indicating the presence of a tumor suppressor gene(s) in this chromosomal region. However, no reasonable candidate has been identified so far. In this study, we report the cloning and functional characterization of a novel mitochondrial protein with tumor suppressor activity, henceforth designated MITOSTATIN. Human MITOSTATIN was found within a 3.2-kb transcript, which encoded a ∼62 kDa, ubiquitously expressed protein with little homology to any known protein. We found homozygous deletions and mutations of MITOSTATIN gene in ∼5 and ∼11% of various cancer-derived cells and solid tumors, respectively. When transiently overexpressed, MITOSTATIN inhibited colony formation, tumor cell growth and was proapoptotic, all features shared by established tumor suppressor genes. We discovered a specific link between MITOSTATIN overexpression and downregulation of Hsp27. Conversely, MITOSTATIN knockdown cells showed an increase in cell growth and cell survival rates. Finally, MITOSTATIN expression was significantly reduced in primary bladder and breast tumors, and its reduction was associated with advanced tumor stages. Our findings support the hypothesis that MITOSTATIN has many hallmarks of a classical tumor suppressor in solid tumors and may play an important role in cancer development and progression.
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Abbreviations
- GFP:
-
green fluorescent protein
- LOH:
-
loss of heterozygosity
References
Anesti V, Scorrano L . (2006). The relationship between mitochondrial shape and function and the cytoskeleton. Biochim Biophys Acta 1757: 692–699.
Aubele M, Mattis A, Zitzelsberger H, Walch A, Kremer M, Hutzler P et al. (1999). Intratumoral heterogeneity in breast carcinoma revealed by laser-microdissection and comparative genomic hybridization. Cancer Genet Cytogenet 110: 94–102.
Aubele MM, Cummings MC, Mattis AE, Zitzelsberger HF, Walch AK, Kremer M et al. (2000). Accumulation of chromosomal imbalances from intraductal proliferative lesions to adjacent in situ and invasive ductal breast cancer. Diagn Mol Pathol 9: 14–19.
Bourgeron T, Chretien D, Rotig A, Munnich A, Rustin P . (1992). Isolation and characterization of mitochondria from human B lymphoblastoid cell lines. Biochem Biophys Res Commun 186: 16–23.
Bruey JM, Paul C, Fromentin A, Hilpert S, Arrigo AP, Solary E et al. (2000). Differential regulation of HSP27 oligomerization in tumor cells grown in vitro and in vivo. Oncogene 19: 4855–4863.
Cereghetti GM, Scorrano L . (2006). The many shapes of mitochondrial death. Oncogene 25: 4717–4724.
Cornford PA, Dodson AR, Parsons KF, Desmond AD, Woolfenden A, Fordham M et al. (2000). Heat shock protein expression independently predicts clinical outcome in prostate cancer. Cancer Res 60: 7099–7105.
Csordas G, Santra M, Reed CC, Eichstetter I, McQuillan DJ, Gross D et al. (2000). Sustained down-regulation of the epidermal growth factor receptor by decorin. A mechanism for controlling tumor growth in vivo. J Biol Chem 275: 32879–32887.
De Vos K, Goossens V, Boone E, Vercammen D, Vancompernolle K, Vandenabeele P et al. (1998). The 55-kDa tumor necrosis factor receptor induces clustering of mitochondria through its membrane-proximal region. J Biol Chem 273: 9673–9680.
Dimmer KS, Navoni F, Casarin A, Trevisson E, Endele S, Winterpacht A et al. (2008). LETM1, deleted in Wolf Hirschhorn syndrome is required for normal mitochondrial morphology and cellular viability. Hum Mol Genet 17: 201–214.
Ehrenfried JA, Herron BE, Townsend Jr CM, Evers BM . (1995). Heat shock proteins are differentially expressed in human gastrointestinal cancers. Surg Oncol 4: 197–203.
Field JK, Kiaris H, Risk JM, Tsiriyotis C, Adamson R, Zoumpourlis V et al. (1995). Allelotype of squamous cell carcinoma of the head and neck: fractional allele loss correlates with survival. Br J Cancer 72: 1180–1188.
Frieden M, James D, Castelbou C, Danckaert A, Martinou JC, Demaurex N . (2004). Ca2+ homeostasis during mitochondrial fragmentation and perinuclear clustering induced by hFis1. J Biol Chem 279: 22704–22714.
Goldoni S, Iozzo RA, Kay P, Campbell S, McQuillan A, Agnew C et al. (2007). A soluble ectodomain of LRIG1 inhibits cancer cell growth by attenuating basal and ligand-dependent EGFR activity. Oncogene 26: 368–381.
Hanahan D, Weinberg RA . (2000). The hallmarks of cancer. Cell 100: 57–70.
Iozzo RV . (1998). Matrix proteoglycans: from molecular design to cellular function. Annu Rev Biochem 67: 609–652.
Jiang F, Richter J, Schraml P, Bubendorf L, Gasser T, Sauter G et al. (1998). Chromosomal imbalances in papillary renal cell carcinoma: genetic differences between histological subtypes. Am J Pathol 153: 1467–1473.
Kamada M, So A, Muramaki M, Rocchi P, Beraldi E, Gleave M . (2007). Hsp27 knockdown using nucleotide-based therapies inhibit tumor growth and enhance chemotherapy in human bladder cancer cells. Mol Cancer Ther 6: 299–308.
Kimura M, Furukawa T, Abe T, Yatsuoka T, Youssef EM, Yokoyama T et al. (1998). Identification of two common regions of allelic loss in chromosome arm 12q in human pancreatic cancer. Cancer Res 58: 2456–2460.
Knudson AG . (2000). Chasing the cancer demon. Annu Rev Genet 34: 1–19.
Koo SH, Kwon KC, Ihm CH, Jeon YM, Park JW, Sul CK . (1999). Detection of genetic alterations in bladder tumors by comparative genomic hybridization and cytogenetic analysis. Cancer Genet Cytogenet 110: 87–93.
Langdon SP, Rabiasz GJ, Hirst GL, King RJ, Hawkins RA, Smyth JF et al. (1995). Expression of the heat shock protein HSP27 in human ovarian cancer. Clin Cancer Res 1: 1603–1609.
Lebret T, Watson RW, Molinie V, O’Neill A, Gabriel C, Fitzpatrick JM et al. (2003). Heat shock proteins HSP27, HSP60, HSP70, and HSP90: expression in bladder carcinoma. Cancer 98: 970–977.
Love S, King RJ . (1994). A 27 kDa heat shock protein that has anomalous prognostic powers in early and advanced breast cancer. Br J Cancer 69: 743–748.
Mehlen P, Schulze-Osthoff K, Arrigo AP . (1996). Small stress proteins as novel regulators of apoptosis. Heat shock protein 27 blocks Fas/APO-1- and staurosporine-induced cell death. J Biol Chem 271: 16510–16514.
Monami G, Gonzalez EM, Hellman M, Gomella LG, Baffa R, Iozzo RV et al. (2006). Proepithelin promotes migration and invasion of 5637 bladder cancer cells through the activation of ERK1/2 and the formation of a paxillin/FAK/ERK complex. Cancer Res 66: 7103–7110.
Moscatello DK, Santra M, Mann DM, McQuillan DJ, Wong AJ, Iozzo RV . (1998). Decorin suppresses tumor cell growth by activating the epidermal growth factor receptor. J Clin Invest 101: 406–412.
Nishizawa M, Izawa I, Inoko A, Hayashi Y, Nagata K, Yokoyama T et al. (2005). Identification of trichoplein, a novel keratin filament-binding protein. J Cell Sci 118: 1081–1090.
Parcellier A, Schmitt E, Gurbuxani S, Seigneurin-Berny D, Pance A, Chantome A et al. (2003). HSP27 is a ubiquitin-binding protein involved in I-kappaBalpha proteasomal degradation. Mol Cell Biol 23: 5790–5802.
Peruzzi F, Prisco M, Dews M, Salomoni P, Grassilli E, Romano G et al. (1999). Multiple signaling pathways of the insulin-like growth factor 1 receptor in protection from apoptosis. Mol Cell Biol 19: 7203–7215.
Rijken AM, Hu J, Perlman EJ, Morsberger LA, Long P, Kern SE et al. (1999). Genomic alterations in distal bile duct carcinoma by comparative genomic hybridization and karyotype analysis. Genes Chromosomes Cancer 26: 185–191.
Rocchi P, Beraldi E, Ettinger S, Fazli L, Vessella RL, Nelson C et al. (2005). Increased Hsp27 after androgen ablation facilitates androgen-independent progression in prostate cancer via signal transducers and activators of transcription 3-mediated suppression of apoptosis. Cancer Res 65: 11083–11093.
Rocchi P, So A, Kojima S, Signaevsky M, Beraldi E, Fazli L et al. (2004). Heat shock protein 27 increases after androgen ablation and plays a cytoprotective role in hormone-refractory prostate cancer. Cancer Res 64: 6595–6602.
Santra M, Mann DM, Mercer EW, Skorski T, Calabretta B, Iozzo RV . (1997). Ectopic expression of decorin protein core causes a generalized growth suppression in neoplastic cells of various histogenetic origin and requires endogenous p21, an inhibitor of cyclin-dependent kinases. J Clin Invest 100: 149–157.
Santra M, Skorski T, Calabretta B, Lattime EC, Iozzo RV . (1995). De novo decorin gene expression suppresses the malignant phenotype in human colon cancer cells. Proc Natl Acad Sci USA 92: 7016–7020.
Sattler HP, Rohde V, Bonkhoff H, Zwergel T, Wullich B . (1999). Comparative genomic hybridization reveals DNA copy number gains to frequently occur in human prostate cancer. Prostate 39: 79–86.
Schmutte C, Baffa R, Veronese LM, Murakumo Y, Fishel R . (1997). Human thymine-DNA glycosylase maps at chromosome 12q22–q24.1: a region of high loss of heterozygosity in gastric cancer. Cancer Res 57: 3010–3015.
Shiseki M, Kohno T, Adachi J, Okazaki T, Otsuka T, Mizoguchi H et al. (1996). Comparative allelotype of early and advanced stage non-small cell lung carcinomas. Genes Chromosomes Cancer 17: 71–77.
Smirnova E, Shurland DL, Ryazantsev SN, van der Bliek AM . (1998). A human dynamin related protein controls the distribution of mitochondria. J Cell Biol 143: 351–358.
Takashi M, Katsuno S, Sakata T, Ohshima S, Kato K . (1998). Different concentrations of two small stress proteins, alphaB crystallin and HSP27 in human urological tumor tissues. Urol Res 26: 395–399.
Tirkkonen M, Johannsson O, Agnarsson BA, Olsson H, Ingvarsson S, Karhu R et al. (1997). Distinct somatic genetic changes associated with tumor progression in carriers of BRCA1 and BRCA2 germ-line mutations. Cancer Res 57: 1222–1227.
Vecchione A, Ishii H, Baldassarre G, Bassi P, Trapasso F, Alder H et al. (2002). FEZ1/LZTS1 is down-regulated in high-grade bladder cancer, and its restoration suppresses tumorigenicity in transitional cell carcinoma cells. Am J Pathol 160: 1345–1352.
Xu G, Guimond MJ, Chakraborty C, Lala PK . (2002). Control of proliferation, migration, and invasiveness of human extravillous trophoblast by decorin, a decidual product. Biol Reprod 67: 681–689.
Acknowledgements
We thank Florencia Bullrich for the FISH analysis, Jonathan Brody for providing CAPAN1 cells and Jason Zoeller for help with the phylogenetic tree. Dr Scorrano is a Senior Scientist of the Dulbecco-Telethon Institute. GenBank=GenBank accession number AY007230. NCBI Protein Database=NCB accession number AAG12971. This study was in part supported by the Sidney Kimmel Foundation for Cancer Research, the Benjamin Perkins Bladder Cancer Fund and the Martin Greitzer Fund (to RB), by Telethon Italy and AIRC Italy (to LS), the National Institutes of Health Grants RO1 CA39481, RO1 CA47282 and RO1 CA120975 (to RVI), RO1 DK068419 (to AM).
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Vecchione, A., Fassan, M., Anesti, V. et al. MITOSTATIN, a putative tumor suppressor on chromosome 12q24.1, is downregulated in human bladder and breast cancer. Oncogene 28, 257–269 (2009). https://doi.org/10.1038/onc.2008.381
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DOI: https://doi.org/10.1038/onc.2008.381
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