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

Abstract

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.

Pathobiology of actinic keratosis: Ultraviolet-dependent keratinocyte proliferation

“…67 A subsequent study reported that expression of BRM and BRG1 proteins was reduced approximately 10-fold in 100% of SCC (n = 11) and BCC (n = 5) specimens, but not in AK (n = 11) samples, which were similar to normal-appearing skin (n = 9). 68 These data suggest that loss of BRM and BRG1 expression is a late and necessary event in the progression of nonmelanoma skin cancer. 68 SUMMARY Environmental exposures to UVradiation initiate a multifactorial cascade of molecular, cellular, viral, immune, and genetic events that influence the progression of AK to malignancy.…”

“…68 These data suggest that loss of BRM and BRG1 expression is a late and necessary event in the progression of nonmelanoma skin cancer. 68 SUMMARY Environmental exposures to UVradiation initiate a multifactorial cascade of molecular, cellular, viral, immune, and genetic events that influence the progression of AK to malignancy. Although particular alterations in gene expression are strongly associated with invasive SCC, there is no mechanism to predict which AKs are at increased risk for malignant progression to invasive SCC.…”

Roles of SWI/SNF Complex Genes in Breast Cancer

“…At least haploinsufficiency of BRG1 is recognized [25][26][27]62], while further studies are necessary whether such a role exists for STK11/LKB1 or not. Similar to BRG1, abnormalities of BRM in various cancers have been reported [58][59][60][61][63][64][65][66][67][68][69]. Though the early studies of cell lines and animal models strongly suggested subunits of SWI/SNF proteins as tumor suppressor, the first definitive evidence that members of these complexes function as tumor suppressive was shown by Versteege and colleagues.…”

“…Some of the studies included genetic analysis of STK11/LKB1 and showed mutation in a subset of tumors especially related with Peutz-Jeugher Syndrome such as breast, colorectal, lung, pancreatic, biliary and ovarian cancer [41][42][43][44][45][46][47][48][49]. On the other hand, quite a lot of studies reported mutations and/or loss or various alterations of BRG1 in human cancer lines and primary tumors [50][51][52][53][54][55][56][57][58][59][60][61]. Thus genes at this chromosomal locus may involve in various type cancer exclusively or in cooperation in some cancer types.…”

Lichtbedingte Schädigungen: Vorboten von aktinischer Keratose und frühem Plattenepithelkarzinom

“…Studien, in denen nach BRM-Mutationen in primären Hauttumoren gesucht wurde, haben beim SCC und beim BCC eine Hotspot-Mutation identifiziert, deren Ursache UV-A-Strahlen sein könnten [8]. Die Untersuchung der BRM-und BRG-1-Proteine hat den Verlust der beiden Proteine beim SCC, nicht aber bei AK ergeben, was darauf hindeutet, dass Mutationen in diesem Gen erst in einem späteren Stadium der Progression von AK zum SCC auftreten [9]. Untersuchungen an gentechnisch veränderten Mäusen haben bestätigt, dass die Depletion von BRM den Schutz der Haut vor Photokarzinogenese abschwächt [10].…”