Malignant pleural mesotheliomas (MPMs) often show CDKN2A and NF2 inactivation, but other highly recurrent mutations have not been described. To identify additional driver genes, we used an integrated genomic analysis of 53 MPM tumor samples to guide a focused sequencing effort that uncovered somatic inactivating mutations in BAP1 in 23% of MPMs. The BAP1 nuclear deubiquitinase is known to target histones (together with ASXL1 as a Polycomb repressor subunit) and the HCF1 transcriptional co-factor, and we show that BAP1 knockdown in MPM cell lines affects E2F and Polycomb target genes. These findings implicate transcriptional deregulation in the pathogenesis of MPM.

Depletion of the mitochondrial genome is involved in several human diseases, as well as in mitochondrial diseases induced by drug therapies used in the treatment of cancer and human immunodeficiency virus. In order to identify the molecular changes underlying the pathogenesis of mitochondrial diseases, we determined the oxidative status of a human cell line following depletion of the mitochondrial genome (denoted rho0 cells). Our analysis revealed that rho0 cells contained approximately 10-fold lower levels of superoxide than parental cells (rho+), as detected by oxidation of dihydroethidium. No concurrent decrease in oxidation of hydrogen peroxide, detected using the dye dichloroflorescein diacetate, was observed in rho0 cells. Depletion of the mitochondrial genome did not affect either the expression of superoxide dismutase or its activity. However, catalase expression and its activity decreased in rho0 cells. In addition, glutathione peroxidase activity was higher in rho0 cells compared with rho+. rho0 cells showed increased lipid peroxidation, increased oxidative damage to the nuclear genome and impaired DNA repair. Our data illustrate the importance of the mitochondrial genome and its function to the cellular oxidative environment and nuclear genome instability. It also provides insights into the development of mitochondrial disease as a consequence of cancer therapy.

BackgroundThe interaction of nuclear and mitochondrial genes is an essential feature in maintenance of normal cellular function. Of 82 structural subunits that make up the oxidative phosphorylation system in the mitochondria, mitochondrial DNA (mtDNA) encodes 13 subunits and rest of the subunits are encoded by nuclear DNA. Mutations in mitochondrial genes encoding the 13 subunits have been reported in a variety of cancers. However, little is known about the nuclear response to impairment of mitochondrial function in human cells.ResultsWe isolated a Rho0 (devoid of mtDNA) derivative of a breast cancer cell line. Our study suggests that depletion of mtDNA results in oxidative stress, causing increased lipid peroxidation in breast cancer cells. Using a cDNA microarray we compared differences in the nuclear gene expression profile between a breast cancer cell line (parental Rho+) and its Rho0 derivative impaired in mitochondrial function. Expression of several nuclear genes involved in cell signaling, cell architecture, energy metabolism, cell growth, apoptosis including general transcription factor TFIIH, v-maf, AML1, was induced in Rho0 cells. Expression of several genes was also down regulated. These include phospholipase C, agouti related protein, PKC gamma, protein tyrosine phosphatase C, phosphodiestarase 1A (cell signaling), PIBF1, cytochrome p450, (metabolism) and cyclin dependent kinase inhibitor p19, and GAP43 (cell growth and differentiation).ConclusionsMitochondrial impairment in breast cancer cells results in altered expression of nuclear genes involved in signaling, cellular architecture, metabolism, cell growth and differentiation, and apoptosis. These genes may mediate the cross talk between mitochondria and the nucleus.