HLTF gene silencing in human colon cancer

Chromatin remodeling enzymes are increasingly implicated in a variety of important cellular functions. Various components of chromatin remodeling complexes, including several members of the SWI/SNF family, have been shown to be disrupted in cancer. In this study we identified as a target for gene inactivation in colon cancer the gene for helicase-like transcription factor (HLTF), a SWI/SNF family protein. Loss of HLTF expression accompanied by HLTF promoter methylation was noted in nine of 34 colon cancer cell lines. In these cell lines HLTF expression was restored by treatment with the demethylating agent 5-azacytidine. In further studies of primary colon cancer tissues, HLTF methylation was detected in 27 of 63 cases (43%). No methylation of HLTF was detected in breast or lung cancers, suggesting selection for HLTF methylation in colonic malignancies. Transfection of HLTF suppressed 75% of colony growth in each of three different HLTF-deficient cell lines, but showed no suppressive effect in any of three HLTF-proficient cell lines. These findings show that HLTF is a common target for methylation and epigenetic gene silencing in colon cancer and suggest HLTF is a candidate colon cancer suppressor gene.

[1]  J. Issa.  The Epigenetics of Colorectal Cancer , 2000, Current opinion in gastroenterology.

[2]  J. Thorner,et al.  High Affinity Interaction of Yeast Transcriptional Regulator, Mot1, with TATA Box-binding Protein (TBP)* , 2001, The Journal of Biological Chemistry.

[3]  J. Lutterbaugh,et al.  Detection of aberrantly methylated hMLH1 promoter DNA in the serum of patients with microsatellite unstable colon cancer. , 2001, Cancer research.

[4]  F. Bosman,et al.  Methylation Silencing and Mutations of the p14ARF and p16INK4a Genes in Colon Cancer , 2001, Laboratory Investigation.

[5]  A. Deimling,et al.  INI1 mutations in meningiomas at a potential hotspot in exon 9 , 2001, British Journal of Cancer.

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

[7]  T. Kinoshita,et al.  HSNF5/INI1 gene mutations in lymphoid malignancy. , 2000, Cancer genetics and cytogenetics.

[8]  P. Sudarsanam,et al.  The Swi/Snf family nucleosome-remodeling complexes and transcriptional control. , 2000, Trends in genetics : TIG.

[9]  M. Caligiuri,et al.  Aberrant CpG-island methylation has non-random and tumour-type–specific patterns , 2000, Nature Genetics.

[10]  N. Ahuja,et al.  Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Issa Jp.  CpG-island methylation in aging and cancer. , 2000 .

[12]  M. Yaniv,et al.  ATP-dependent chromatin remodelling: SWI/SNF and Co. are on the job. , 1999, Journal of molecular biology.

[13]  J. Issa,et al.  Aging, DNA methylation and cancer. , 1999, Critical reviews in oncology/hematology.

[14]  J. Herman,et al.  CpG island methylator phenotype in colorectal cancer. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Hao Ding,et al.  Functional Interactions between Sp1 or Sp3 and the Helicase-like Transcription Factor Mediate Basal Expression from the Human Plasminogen Activator Inhibitor-1 Gene* , 1999, The Journal of Biological Chemistry.

[16]  Hiroki Inui,et al.  Mutations of a novel human RAD54 homologue, RAD54B, in primary cancer , 1999, Oncogene.

[17]  L. Kasturi,et al.  Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[18]  Olivier Delattre,et al.  Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer , 1998, Nature.

[19]  J. Herman,et al.  Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[20]  N. Rosenthal,et al.  Developmental regulation of Zbu1, a DNA-binding member of the SWI2/SNF2 family. , 1997, Developmental biology.

[21]  K. Kinzler,et al.  Lessons from Hereditary Colorectal Cancer , 1996, Cell.

[22]  J. Herman,et al.  Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[23]  L. Nelles,et al.  Characterization of a helicase-like transcription factor involved in the expression of the human plasminogen activator inhibitor-1 gene. , 1996, DNA and cell biology.

[24]  J. Herman,et al.  Hypermethylation-associated inactivation indicates a tumor suppressor role for p15INK4B. , 1996, Cancer research.

[25]  J A Eisen,et al.  Evolution of the SNF2 family of proteins: subfamilies with distinct sequences and functions. , 1995, Nucleic acids research.

[26]  K. Kinzler,et al.  Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. , 1995, Science.

[27]  G. Evans,et al.  The HIP116 SNF2/SW12-related transcription factor gene (SNF2L3) is located on human chromosome 3q25.1-q26.1. , 1995, Genomics.

[28]  R. Perry,et al.  DNA-binding and chromatin localization properties of CHD1 , 1995, Molecular and cellular biology.

[29]  P. Sheridan,et al.  Cloning of an SNF2/SWI2-related Protein That Binds Specifically to the SPH Motifs of the SV40 Enhancer and to the HIV-1 Promoter (*) , 1995, The Journal of Biological Chemistry.

[30]  J. Willson,et al.  TGF-beta 1 is an autocrine-negative growth regulator of human colon carcinoma FET cells in vivo as revealed by transfection of an antisense expression vector , 1992, The Journal of cell biology.

[31]  D. Glover,et al.  Chromosome tangling and breakage at anaphase result from mutations in lodestar, a Drosophila gene encoding a putative nucleoside triphosphate-binding protein. , 1991, Genes & development.