Alterations of the SWI/SNF chromatin remodelling subunit-BRG1 and BRM in hepatocellular carcinoma.

The SWI/SNF chromatin remodelling complex, which contains either brahma-related gene-1 (BRG1) or brahma (BRM) as the catalytic ATPase, functions as a master regulator of gene expression. To examine alterations of BRG1 and BRM in hepatocellular carcinoma (HCC). We investigated DNA copy number aberrations in human HCC cell lines using a high-density oligonucleotide microarray. We determined DNA copy numbers and expression levels of BRG1 and BRM genes in primary HCC tumours, and conducted further searches for mutations in BRG1 and BRM genes. Homozygous deletion of the BRG1 gene was found in HCC cell line SNU398. Copy number losses of BRG1 and BRM genes were observed in 14 (26%) and 7 (13%) of 54 primary HCC tumours respectively. We found four somatic missense mutations in the BRG1 gene in two of 36 primary HCC tumours, but no mutations in BRM gene. Expression of BRM mRNA, but not BRG1 mRNA, was significantly reduced in primary HCC tumours, compared to non-tumour tissue counterparts. Immunohistochemical analyses of non-tumour liver tissues showed that BRM protein was expressed in hepatocytes and bile-duct epithelial cells, whereas BRG1 protein was expressed in bile-duct epithelial cells, but not in hepatocytes. BRM protein expression was lost in nine (22.5%) of 40 HCC tumours. Loss of BRM protein expression was significantly associated with poor overall survival. Reduced expression of BRM may contribute to the carcinogenesis of HCC. Although deletions and mutations in BRG1 gene were identified, the role of BRG1 in HCC tumourigenesis remains unclear.

Endo M ，Yasui K ，Zen Y ，Gen Y ，Zen K ，Tsuji K ，Dohi O ，Mitsuyoshi H ，Tanaka S ，Taniwaki M ，Nakanuma Y ，Arii S ，Yoshikawa T ... -  《-》

Aberrant expression of SWI/SNF catalytic subunits BRG1/BRM is associated with tumor development and increased invasiveness in prostate cancers.

Brahma gene (BRM) and Brahma-related gene 1 (BRG1) are major components with ATPase enzymatic activities in the nucleosome remodeling SWI/SNF complex, and their expression pattern in human prostate cancers is unknown. We analyzed a published cDNA microarray data set of prostate cancers for the expression of SWI/SNF genes, and then we evaluated the expression levels of BRG1 and BRM proteins with a semi-quantitative immunohistochemistry (IHC) approach in a pairwise manner of malignant versus benign tissues from individual prostate cancers. The correlation of BRG1/BRM expression with clinical parameters was analyzed. Microarray data showed an aberrant expression of BRG1 and BRM but not SNF5/INI1 genes in different stages of the disease course. In immunochemistry studies, BRG1 expression was significantly higher in malignant tissues compared to their benign compartments, and this difference was more profound in high-grade cancers. Although BRM expression showed a heterogeneous pattern, the average level of BRM expression was lower in malignant tissues than that in benign tissues. More interestingly, BRG1 and BRM expression showed a reciprocal pattern in both benign and malignant tissues of individual cases. In malignant tissues, higher BRG1 but not BRM expression levels were associated with larger volume of tumor mass. Increased expression of BRG1 but not BRM protein was observed in invasive cancer cells. Consistently, overexpression of exogenous wild-type BRG1 and BRM but not mutant BRG1 enhanced cancer cell invasion in an in vitro cell invasion assay. We provide the first evidence that aberrant expression of BRG1 and BRM genes is associated with disease development and progression in prostate cancers and increased BRG1 expression may promote tumor growth and invasion.

Sun A ，Tawfik O ，Gayed B ，Thrasher JB ，Hoestje S ，Li C ，Li B ... -  《PROSTATE》

SWI/SNF chromatin-remodeling factors induce changes in DNA methylation to promote transcriptional activation.

Banine F ，Bartlett C ，Gunawardena R ，Muchardt C ，Yaniv M ，Knudsen ES ，Weissman BE ，Sherman LS ... -  《CANCER RESEARCH》

BRM and BRG1 subunits of the SWI/SNF chromatin remodelling complex are downregulated upon progression of benign skin lesions into invasive tumours.

Background  Nonmelanoma skin cancer is caused by exposure to ultraviolet radiation within sunlight. Actinic keratoses (AKs) are benign precursor lesions that can develop into invasive squamous cell carcinoma (SCC). Little is known about the molecular events that lead to human skin cancer progression from benign to invasive. Objectives  To determine novel genes that may be involved in skin cancer progression based on data from an initial microarray screen of human skin cancers. Methods  The SWI/SNF chromatin remodelling ATPase subunit BRM was identified as being downregulated in SCC but not AK compared with normal skin in our microarray screen. Therefore reverse transcription-polymerase chain reaction, gene methylation and protein expression was used to study BRM and its alternative ATPase subunit BRG1 in a range of human skin cancers. Results  We found reduced levels of mRNA coding for BRM but not BRG1 in SCC. BRM mRNA levels in AK were similar to those in normal skin. Deregulation of BRM did not result from hypermethylation of CpG regions in the promoter of these genes. Both BRM and BRG1 protein was reduced by about 10-fold in 100% of SCC and basal cell carcinoma, but not in AK specimens examined. Conclusions  BRM protein may be decreased due to low levels of mRNA, while BRG1 protein loss appears to be post-translational. BRM and BRG1 may be novel tumour suppressor genes for human skin cancer. They appear to be involved after development of benign lesions, and are downregulated during progression towards invasion.

Bock VL ，Lyons JG ，Huang XX ，Jones AM ，McDonald LA ，Scolyer RA ，Moloney FJ ，Barnetson RS ，Halliday GM ... -  《-》

Mammalian chromatin remodeling complex SWI/SNF is essential for enhanced expression of the albumin gene during liver development.

Inayoshi Y ，Miyake K ，Machida Y ，Kaneoka H ，Terajima M ，Dohda T ，Takahashi M ，Iijima S ... -  《JOURNAL OF BIOCHEMISTRY》