7982

ST7

ETS7q|FAM4A|FAM4A1|HELG|RAY1|SEN4|TSG7;suppression of tumorigenicity 7;ST7;suppression of tumorigenicity 7

family with sequence similarity 4, subfamily A, member 1|suppression of tumorigenicity 7 (breast)|suppressor of tumorigenicity 7 protein

7q31.2

protein-coding

Loss of heterozygosity (LOH) of markers on human chromosome 7q31 is frequently encountered in a variety of human neoplasias, indicating the presence of a tumor-suppressor gene (TSG). By a combination of microcell-fusion and deletion-mapping studies, we previously established that this TSG resides within a critical region flanked by the genetic markers D7S522 and D7S677. Using a positional cloning strategy and aided by the availability of near-complete sequence of this genomic interval, we have identified a TSG within 7q31, named ST7 (for suppression of tumorigenicity 7; this same gene was recently reported in another context and called RAY1). ST7 is ubiquitously expressed in human tissues. Analysis of a series of cell lines derived from breast tumors and primary colon carcinomas revealed the presence of mutations in ST7. Introduction of the ST7 cDNA into the prostate-cancer-derived cell line PC3 had no effect on the in vitro proliferation of the cells, but abrogated their in vivo tumorigenicity. Our data indicate that ST7 is a TSG within chromosome 7q31 and may have an important role in the development of some types of human cancer.

We recently identified a novel gene, RAY1 (FAM4A1), which spans a translocation breakpoint at 7q31 in a patient with autism. This gene has more recently been reported to be a suppressor of tumorigenicity, ST7, although controversy surrounds this observation because subsequent reports have failed to corroborate these findings. Our further analysis of this locus reveals that it is composed of a multigene system that includes two noncoding sense strand genes (ST7OT3 and ST7OT4) that overlap with many alternative forms of the coding RAY1/ST7 transcript, and two noncoding genes on the antisense strand (ST7OT1 and ST7OT2). RAY1/ST7 was determined to have at least three different 5 exons with alternative start codons, one of which seems to be used almost exclusively in the brain. We have also identified a third alternative 3 end of RAY1/ST7 that uses exons from ST7OT3. ST7OT3 spans from intron 10 to exon 14 of RAY1/ST7 and includes several exons. ST7OT4 has at least seven exons and is transcribed on the sense strand between RAY1/ST7 exon 1 and a tropomyosin-like sequence, TPM3L2. ST7OT1 overlaps with the RAY1/ST7 exon 1 and promoter. ST7OT2 spans from RAY1/ST7 intron 9 to intron 1, and has multiple isoforms. We screened the exons of RAY1/ST7 and ST7OT1-3 for sequence variants in 90 unrelated autism probands and identified several rare variants, including a Ile361Val substitution. Although these variants were not observed in a control population, it is unclear whether they contribute to the autistic phenotype. We postulate that the apparent noncoding genes at the RAY1/ST7 locus may be regulatory RNAs. The RAY1/ST7 may generate at least 18 possible isoforms, with many more arising if other sense-strand exons from ST7OT3 and ST7 OT4 are used in a selective and possibly tissue-specific manner.

Protein arginine methyltransferases (PRMTs) have been implicated in transcriptional activation and repression, but their role in controlling cell growth and proliferation remains obscure. We have recently shown that PRMT5 can interact with flag-tagged BRG1- and hBRM-based hSWI/SNF chromatin remodelers and that both complexes can specifically methylate histones H3 and H4. Here we report that PRMT5 can be found in association with endogenous hSWI/SNF complexes, which can methylate H3 and H4 N-terminal tails, and show that H3 arginine 8 and H4 arginine 3 are preferred sites of methylation by recombinant and hSWI/SNF-associated PRMT5. To elucidate the role played by PRMT5 in gene regulation, we have established a PRMT5 antisense cell line and determined by microarray analysis that more genes are derepressed when PRMT5 levels are reduced. Among the affected genes, we show that suppressor of tumorigenicity 7 (ST7) and nonmetastatic 23 (NM23) are direct targets of PRMT5-containing BRG1 and hBRM complexes. Furthermore, we demonstrate that expression of ST7 and NM23 is reduced in a cell line that overexpresses PRMT5 and that this decrease in expression correlates with H3R8 methylation, H3K9 deacetylation, and increased transformation of NIH 3T3 cells. These findings suggest that the BRG1- and hBRM-associated PRMT5 regulates cell growth and proliferation by controlling expression of genes involved in tumor suppression.

Glioblastoma is the most common and aggressive histologic subtype of brain cancer with poor outcomes and limited treatment options. Here, we report the selective overexpression of the protein arginine methyltransferase PRMT5 as a novel candidate theranostic target in this disease. PRMT5 silences the transcription of regulatory genes by catalyzing symmetric dimethylation of arginine residues on histone tails. PRMT5 overexpression in patient-derived primary tumors and cell lines correlated with cell line growth rate and inversely with overall patient survival. genetic attenuation of PRMT5 led to cell-cycle arrest, apoptosis, and loss of cell migratory activity. Cell death was p53-independent but caspase-dependent and enhanced with temozolomide, a chemotherapeutic agent used as a present standard of care. Global gene profiling and chromatin immunoprecipitation identified the tumor suppressor ST7 as a key gene silenced by PRMT5. Diminished ST7 expression was associated with reduced patient survival. PRMT5 attenuation limited PRMT5 recruitment to the ST7 promoter, led to restored expression of ST7 and cell growth inhibition. Finally, PRMT5 attenuation enhanced glioblastoma cell survival in a mouse xenograft model of aggressive glioblastoma. Together, our findings defined PRMT5 as a candidate prognostic factor and therapeutic target in glioblastoma, offering a preclinical justification for targeting PRMT5-driven oncogenic pathways in this deadly disease.

We studied loss of heterozygosity (LOH) in chromosome 7q in order to determine the location of a putative tumor suppressor gene (TSG) in human epithelial ovarian carcinomas. Samples were obtained from 26 primary ovarian carcinomas at the time of staging laparotomy. Paired normal and tumoral DNAs were used as templates for polymerase chain reaction amplification of a set of 14 (C-A)n microsatellite repeats on 7q21-qter. All the cases studied presented LOH at one or more loci on 7q. Seventy-three percent LOH (in 14 of 19 informative cases) were detected in D7S522 at 7q31.1. The percentages of LOH were normally distributed around microsatellite D7S522 determining a smallest common deleted region of 1 cM. The high incidence of LOH in primary ovarian carcinomas suggests that a TSG relevant to the development of ovarian cancers is present at 7q31.1, confirming our previous functional evidence for a TSG in this region.

We studied loss of heterozygosity (LOH) on human chromosome 7q to determine the location of a putative tumor suppressor gene (TSG) in human primary prostate carcinomas. Samples were obtained from 16 primary prostate carcinomas surgically removed from patients at The University of Texas M. D. Anderson cancer Center. Paired normal and tumor DNAs were used as template for PCR amplification of a set of 14 CA microsatellite repeats on 7q21-qter. Twelve of 16 cases studied had LOH at one or more loci on 7q. Eighty-three percent LOH (five of six informative cases) was detected with D7S522 at 7q31.1-7q31.2. Percentage of LOH was normally distributed around D7S522. The high incidence of LOH in primary prostate carcinomas suggests that there is a TSG relevant to the development of prostate cancers at 7q31.1-31.2, confirming our previous functional evidence for a TSG at this location. Further research needs to be conducted to establish the identity and function of this putative TSG.

We have identified previously a putative tumor suppressor gene (TSG) locus at human chromosome (hchr) 7q31 showing that it is altered in a variety of human epithelial tumors. To determine whether this TSG is conserved in mice, we studied loss of heterozygosity (LOH) in chemically induced mouse liver adenomas. The LOH analysis was performed by polymerase chain reaction amplification of 17 (CA)n microsatellite repeats on mouse chromosome (mchr) 6 A2-C3. Ninety-six of 106 cases (90.6%) had LOH at D6Mit50, and 89.5% had LOH at D6Mit179. These two loci are 0.2 cM apart on mchr 6A2. Another high-LOH site was found in the C3 band. The high incidence of LOH in the 7q-homologous segment of mchr 6 indicates that the human TSG is conserved and is involved in the development of hepatomas.