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 over-expressed, MITOSTATIN inhibited colony formation, tumor cell growth and was pro-apoptotic, all features shared by established tumor suppressor genes. We discovered a specific link between MITOSTATIN over-expression and down-regulation of Hsp27. Conversely MITOSTATIN knock-down 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.

Decorin Induces Mitophagy in Breast Carcinoma Cells via Peroxisome Proliferator-activated Receptor γ Coactivator-1α (PGC-1α) and Mitostatin

“…Consistent with reports utilizing urothelial and prostate carcinoma cells (55), decorin induces mitostatin in basal breast carcinoma cells where it rapidly accumulates, beginning at 30 min and remains elevated for up to 4 h. Importantly, an antagonistic relationship existed for regulation of mitostatin via the HGF/Met axis. Image analysis revealed a surprising and unexpected subcellular localization of mitostatin; that is, after decorin treatment; mitostatin localized to large (2-3 m) perinuclear structures reminiscent of autophagosomes.…”

“…Consistent with the proclivity of decorin to induce tumor suppressor genes (PEG3, CDKN1A), decorin induces mitostatin, a mitochondrial protein with oncostatic activity (55). Upon induction, mitostatin displays several hallmarks of a classical tumor suppressor gene such as inhibiting tumor cell migration, growth, and proliferation and simultaneously triggering proapoptotic pathways (55,56).…”

“…Dulbecco's phosphate buffer saline was purchased from Corning (Tewksbury, MA). The anti-mitostatin affinity rabbit purified antibody was described before (55). The rabbit antibodies against PGC-1␣ and voltage-dependent anion channel (VDAC) were from Abcam Inc. (Boston, MA).…”

“…Upon induction, mitostatin displays several hallmarks of a classical tumor suppressor gene such as inhibiting tumor cell migration, growth, and proliferation and simultaneously triggering proapoptotic pathways (55,56). Furthermore, mitostatin is absent in ϳ35% of human prostate carcinomas (56), whereas decreased expression is associated with advanced cancer stages (55).…”

Mutational Analysis of MITOSTATIN, a Candidate Tumor-Suppressor Gene, at a Mononucleotide Repeat in Gastric and Colorectal Carcinoma

“…1 The MITOSTATIN gene is somatically mutated in cancer cell lines (gastric, prostate and pancreas cell lines) and is down-regulated in bladder and breast cancer tissues. 1 2 There is a polyadenine tract (A8) in the exon 5 of the MITO-STATIN gene, but the frameshift mutation at this site is not known.…”