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MITOSTATIN, a putative tumor suppressor on chromosome 12q24.1, is downregulated in human bladder and breast cancer

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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Accession codes

Accessions

GenBank/EMBL/DDBJ

Abbreviations

GFP:

green fluorescent protein

LOH:

loss of heterozygosity

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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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Correspondence to R Baffa.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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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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