Decreased expression of the SIN3A gene, a candidate tumor suppressor located at the prevalent allelic loss region 15q23 in non-small cell lung cancer.

To identify the tumor suppressor genes (TSG) associated with non-small cell lung cancers (NSCLC), we performed the loss of heterozygosity (LOH) analysis in NSCLC samples from 66 patients. We focused on the novel hot spot region on 15q14-24 with eight polymorphic microsatellite markers. Frequent allelic loss was detected in 33 of 48 informative cases (69%) at D15S984 on 15q23. We defined the fine map on the region and identified the SIN3A gene as a candidate TSG. The SIN3A gene product is a component of the histone deacetylase (HDAC) complex and plays essential roles in early embryonic development and the proliferation and survival of a variety of cells through the repression of diverse signaling pathways. Our expression analysis revealed more frequent down-regulation of the SIN3A mRNA in 19 of 31 cases (61%) of NSCLCs in comparison to those of other flanking genes (16-42%), albeit the correlation of the decreased expression with the LOH did not attain statistic significance. These results suggest that the attenuated function of SIN3A due to a decreased level of expression may result in epigenetic de-regulation of growth-related genes through histone acetylation, which leads to the tumorigenesis of lung cancer cells. To our knowledge, this is the first evidence of the down-regulation of the SIN3A gene in human cancer.

[1]  S. Nishioka,et al.  Genomic structure of the human ING1 gene and tumor-specific mutations detected in head and neck squamous cell carcinomas. , 2000, Cancer research.

[2]  S. Lam,et al.  High resolution chromosome 3p allelotyping of human lung cancer and preneoplastic/preinvasive bronchial epithelium reveals multiple, discontinuous sites of 3p allele loss and three regions of frequent breakpoints. , 2000, Cancer research.

[3]  A. Levine,et al.  Transcriptional repression by wild-type p53 utilizes histone deacetylases, mediated by interaction with mSin3a. , 1999, Genes & development.

[4]  A. Horii,et al.  The Thymine DNA Glycosylase MBD4 Represses Transcription and Is Associated with Methylated p16INK4a and hMLH1 Genes , 2005, Molecular and Cellular Biology.

[5]  J. Minna,et al.  Allelotyping demonstrates common and distinct patterns of chromosomal loss in human lung cancer types , 1998, Genes, chromosomes & cancer.

[6]  D. Trouche,et al.  RB and hbrm cooperate to repress the activation functions of E2F1. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[7]  H. Inoue,et al.  SYT, a partner of SYT-SSX oncoprotein in synovial sarcomas, interacts with mSin3A, a component of histone deacetylase complex , 2004, Laboratory Investigation.

[8]  S. Sunkara,et al.  A novel human DNA glycosylase that removes oxidative DNA damage and is homologous to Escherichia coli endonuclease VIII. , 2002, DNA repair.

[9]  Tony Kouzarides,et al.  Retinoblastoma protein recruits histone deacetylase to repress transcription , 1998, Nature.

[10]  A. Hamburger,et al.  The ErbB3 binding protein Ebp1 interacts with Sin3A to repress E2F1 and AR-mediated transcription , 2005, Nucleic acids research.

[11]  R. Kingston,et al.  Reconstitution of a core chromatin remodeling complex from SWI/SNF subunits. , 1999, Molecular cell.

[12]  A. Knudson.  Mutation and cancer: statistical study of retinoblastoma. , 1971, Proceedings of the National Academy of Sciences of the United States of America.

[13]  Weidong Wang,et al.  Loss of BRG1/BRM in human lung cancer cell lines and primary lung cancers: correlation with poor prognosis. , 2003, Cancer research.

[14]  R. Kingston,et al.  Cooperation between Complexes that Regulate Chromatin Structure and Transcription , 2002, Cell.

[15]  M. Yaniv,et al.  Purification and biochemical heterogeneity of the mammalian SWI‐SNF complex. , 1996, The EMBO journal.

[16]  R. DePinho,et al.  mSin3A corepressor regulates diverse transcriptional networks governing normal and neoplastic growth and survival. , 2005, Genes & development.

[17]  J. Qin,et al.  Identification of a novel BRMS1-homologue protein p40 as a component of the mSin3A/p33(ING1b)/HDAC1 deacetylase complex. , 2004, Biochemical and biophysical research communications.

[18]  S. Toyooka,et al.  Tumor‐specific exon creation of the HELLS/SMARCA6 gene in non‐small cell lung cancer , 2004, International journal of cancer.

[19]  D. Teng,et al.  BRG1, a component of the SWI-SNF complex, is mutated in multiple human tumor cell lines. , 2000, Cancer research.

[20]  H. Inoue,et al.  Significant growth suppression of synovial sarcomas by the histone deacetylase inhibitor FK228 in vitro and in vivo. , 2005, Cancer letters.

[21]  D. Dean,et al.  Rb Interacts with Histone Deacetylase to Repress Transcription , 1998, Cell.

[22]  T. Kundu,et al.  Tumor Suppressor SMAR1 Mediates Cyclin D1 Repression by Recruitment of the SIN3/Histone Deacetylase 1 Complex , 2005, Molecular and Cellular Biology.

[23]  J. Minna,et al.  Allelic losses at chromosome 8p21-23 are early and frequent events in the pathogenesis of lung cancer. , 1999, Cancer research.

[24]  J. Licht,et al.  Histone deacetylases as therapeutic targets in hematologic malignancies. , 2002, Current opinion in hematology.

[25]  D. Reinberg,et al.  RBP1 Recruits the mSIN3-Histone Deacetylase Complex to the Pocket of Retinoblastoma Tumor Suppressor Family Proteins Found in Limited Discrete Regions of the Nucleus at Growth Arrest , 2001, Molecular and Cellular Biology.

[26]  D. Israeli,et al.  Inhibition of presenilin 1 expression is promoted by p53 and p21WAF-1 and results in apoptosis and tumor suppression , 1998, Nature Medicine.

[27]  C. Plass,et al.  HLTF gene silencing in human colon cancer , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[28]  H. Hammes,et al.  RETRACTED: Methylglyoxal Modification of mSin3A Links Glycolysis to Angiopoietin-2 Transcription , 2006, Cell.

[29]  J. Minna,et al.  Genome-wide allelotyping of lung cancer identifies new regions of allelic loss, differences between small cell lung cancer and non-small cell lung cancer, and loci clustering. , 2000, Cancer research.

[30]  Jun O. Liu,et al.  Menin, a tumor suppressor, represses JunD-mediated transcriptional activity by association with an mSin3A-histone deacetylase complex. , 2003, Cancer research.

[31]  T. Gress,et al.  KLF11 mediates a critical mechanism in TGF-beta signaling that is inactivated by Erk-MAPK in pancreatic cancer cells. , 2004, Gastroenterology.

[32]  Colin A. Johnson,et al.  Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex , 1998, Nature.

[33]  L. Magnaghi-Jaulin,et al.  Retinoblastoma protein represses transcription by recruiting a histone deacetylase , 1998, Nature.

[34]  Ji Miao,et al.  Role of an mSin3A-Swi/Snf Chromatin Remodeling Complex in the Feedback Repression of Bile Acid Biosynthesis by SHP , 2004, Molecular and Cellular Biology.

[35]  J. Minna,et al.  Progress in understanding the molecular pathogenesis of human lung cancer. , 1998, Biochimica et biophysica acta.

[36]  J. Minna,et al.  Deletions of chromosome 4 at multiple sites are frequent in malignant mesothelioma and small cell lung carcinoma. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[37]  James R. Downing,et al.  ETO, a Target of t(8;21) in Acute Leukemia, Makes Distinct Contacts with Multiple Histone Deacetylases and Binds mSin3A through Its Oligomerization Domain , 2001, Molecular and Cellular Biology.

[38]  Song Tan,et al.  ING tumor suppressor proteins are critical regulators of chromatin acetylation required for genome expression and perpetuation. , 2006, Molecular cell.

[39]  A. Levine,et al.  Wild-type p53 negatively regulates the expression of a microtubule-associated protein. , 1996, Genes & development.