UQCRH gene encoding mitochondrial Hinge protein is interrupted by a translocation in a soft-tissue sarcoma and epigenetically inactivated in some cancer cell lines

Abstract

We previously reported the identification of a novel zincfinger gene, designated ZSG, fused to Ewing sarcoma gene (EWS) by a submicroscopic paracentric inversion of 22q12 in a small round cell sarcoma presenting a translocation t(1;22)(p34;q12). We report here the molecular cloning and characterization of the breakpoint in 1p34, which encompasses the gene coding for mitochondrial Hinge protein ubiquinol-cytochrome C reductase hinge gene (UQCRH). All the three breakpoints, two on 22q12 and one in 1p34, interrupt different genes: EWS, ZSG and UQCRH. We determined the genomic structure of UQCRH, characterized its splicing variants and identified a transcribed processed pseudogene. The analysis of UQCRH expression in normal tissues and cancer cell lines revealed absent expression of UQCRH in two ovarian and one breast cancer cell lines and reduced expression in a further breast carcinoma cell line. CpG island methylation upstream exon 1 was detected in all the three cell lines with absent expression. Moreover, treatment with demethylating agent 5-azacytidine restored UQCRH expression in OAW42 ovarian cancer cells. These data provide preliminary evidence of the inactivation of UQCRH gene in cancer either by structural rearrangements or epigenetic mechanisms. Oncogene ( Keywords: EWS; sarcoma; ovarian carcinoma; hinge protein; mitochondrial complex III Sarcomas are a heterogeneous group of malignancies of mesenchymal origin that frequently display nonrandom chromosomal translations creating specific fusion genes. The Ewing family of tumors (EFT) comprises small round cell sarcomas showing moderate neural differentiation that were considered in the past as distinct entities: Ewing's sarcoma, primitive neuroectodermal tumors, peripheral neuroepithelioma and Askin tumor. It is now well documented that almost 95% of EFT share the presence of EWS-FLI1 fusion gene, detected cytogenetically as t(11;22)(q24;q12), or of four other alternative Ewing sarcoma gene (EWS) fusions with different partners (namely ERG, ETV1, FEV. E1AF) (Kovar, 1998). Other sarcoma types display specific fusion genes involving EWS and different partners: CHOP (12q13) in myxoid liposarcoma, WT1 (11p13) in intra-abdominal desmoplastic small round cell tumor, CHN/TEC (9q22) in myxoid chondrosarcoma, ATF1 (12q13) in malignant melanoma of soft parts and ZSG/ PATZ (22q12) in a small round cell sarcoma. In all cases, the identification of the translocation by FISH and/or of the fusion transcript by RT-PCR currently offers an invaluable clue for the correct diagnosis. The exact functions of EWS protein, an RNA-binding protein, are still unclear, but it is widely proven by in vitro studies that the EWS-related fusion genes act as dominant oncogenes with aberrant transcription and possibly splicing features (Arvand and Denny, 2001).We previously reported the identification of a novel fusion gene between EWS and the novel putative transcription factor ZSG, generated by an intrachromosomal rearrangement of chromosome 22, an inversion of 22q12, in a small round cel...

High mobility group A-interacting proteins in cancer: focus on chromobox protein homolog 7, homeodomain interacting protein kinase 2 and PATZ

“…In contrast, 5-prime-UQCRH/EWS-3prime and 5-prime-PATZ/UQCRH-3-prime produced out-of-frame transcripts containing premature stop codons. 82 Absence of the wild-type PATZ1 mRNA in tumor tissue supports the observation that the rearrangement of the second PATZ1 allele observed in Southern blot led to a complete loss of wild-type PATZ expression. 77 Kobayashi and coworkers, as well as our group, isolated PATZ by yeast 2-hybrid screenings with the POZ domain of Bach2 or the RING finger protein-4 (RNF4) as baits, respectively.…”

High mobility group A-interacting proteins in cancer: focus on chromobox protein homolog 7, homeodomain interacting protein kinase 2 and PATZ

“…In contrast, 5-prime-UQCRH/EWS-3-prime and 5-prime-PATZ/UQCRH-3-prime produced out-of-frame transcripts containing premature stop codons. 82 Absence of the wild-type PATZ1 mRNA in tumor tissue supports the observation that the rearrangement of the second PATZ1 allele observed in Southern blot led to a complete loss of wild-type PATZ expression. 77 Kobayashi and coworkers, as well as our group, isolated PATZ by yeast 2-hybrid screenings with the POZ domain of Bach2 or the RING finger protein-4 (RNF4) as baits, respectively.…”

Comprehensive molecular characterization of clear cell renal cell carcinoma

“…The top-ranked gene by inverse correlation between gene expression and DNA methylation was UQCRH , hypermethylated in 36% of the tumors. UQCRH has been previously suggested to be a tumor suppressor 14 , but not linked to ccRCC. Interestingly, increasing promoter hypermethylation frequency correlated with higher stage and grade (Figure 2a, b).…”