Expression of p270 (ARID1A), a component of human SWI/SNF complexes, in human tumors

Abstract

Human SWI/SNF complexes use the energy of ATP hydrolysis to remodel chromosomes and alter gene expression patterns. The activity of the complexes generally promotes tissue-specific gene expression and restricts cell proliferation. The ATPase that drives the complexes, BRG1, is essential for tumor suppression in mice and deficient in a variety of established human tumor cell lines. The complex contains at least 7 other core components, one of which is a large subunit designated p270. p270 RNA is expressed in all normal human tissues examined, but protein expression is severely reduced in at least 2 human tumor lines, C33A and T47D. We show here that loss of p270 in the C33A and T47D cell lines is evident at the RNA level as well as the protein level. The implication that p270 can be informatively screened at the RNA level made a high-efficiency cancer profiling array approach to screening human tumors feasible. Expression was screened in an array containing RNA-derived cDNA from 241 tumor and corresponding matched normal tissues from individual patients. p270 deficiency was observed at a higher overall frequency than BRG1 deficiency, but all tissues were not equally affected. Deficiency of p270 was observed most frequently in carcinomas of the breast and kidney. The results were most striking in kidney, where p270 expression was deficient in 30% of carcinoma samples screened. Key words: p270; SWI/SNF; kidney cancer; breast cancer; tumor suppressionHuman SWI/SNF complexes are transcription-regulating complexes that are essential to normal differentiation and development. They also play a vital role in the control of cell proliferation and suppression of carcinogenesis (reviewed by Klochendler-Yeivin and Yaniv 1 and by Muchardt and Yaniv 2 ). The complexes can vary in composition, but all are able to remodel chromatin structure through ATP-dependent mechanisms. [3][4][5][6][7] ATPase activity, which is DNA-dependent, resides in the SWI2/SNF2 enzyme in yeast and in the SWI2/SNF2-related proteins BRG1 and hBRM in humans. Shortly after BRG1 was cloned on the basis of its homology to the Drosophila and yeast ATPases, 8 it became apparent that BRG1 is occasionally found at low or undetectable levels in common tumor-derived laboratory lines. 2,9,10 This suggestion that loss of BRG1 may be a causative factor in human tumorigenesis is strongly supported by the enhanced tumor susceptibility of BRG1 heterozygous mice; tumors of epithelial origin were observed in the head and inguinal regions of these mice. 11 Additional components of the complex are also likely to be vital for tumor suppression. The hSNF5 complex component (also designated INI1 or BAF47) is lost with high frequency in specific types of human tumors, primarily pediatric rhabdoid tumors, 12-15 and Snf5-deficient mice also develop tumors at an early age. 16,17 BRG1-associated factor-155 (BAF155) is occasionally deficient in tumor cell lines, 10 and BAF155-null mouse embryos die at an early implantation stage, indicating the gene is required for normal developm...

The SWI/SNF complex and cancer

“…ARID1A is located in 1p36.11 (Kozmik et al, 2001), a region frequently deleted in human cancers (Huang et al, 2007), and may be involved in cancer development. BAF250A is lost in two cell lines, C33a and T47D , and may be deficient in as many as 30% of renal carcinomas and 10% of breast carcinomas (Wang et al, 2004a). ARID1A-and ARID1B-containing SWI/SNF complexes appear to have antagonistic effects on cell cycle progression, with ARID1A participating in repression and ARID1B in the induction of key cell cycle regulators such as c-MYC (Nagl et al, 2006(Nagl et al, , 2007.…”

The role of components of the chromatin modification machinery in carcinogenesis of clear cell carcinoma of the ovary (Review)

“…ARID1A is one of the most frequently deleted genes across all cancer types (23,24) and knockdown of this gene results in a failure of cell cycle arrest (23,25). This alteration strongly predominates in kidney, breast and lung cancers in humans (13,26). All inactivating mutations of this gene have been found in these cancers, suggesting that ARID1A plays an essential role during cancer development as a tumor suppressor.…”

“…Loss of the ARID1A protein may cause a failure to regulate the H2B assembly, resulting in accumulation of H2B to high levels. Results using siRNA-knockdown approach indicate that ARID1A is required for cell-cycle arrest (26). Ubiquitination of H2B was associated with transcriptional activation (45).…”

Loss of ARID1A/BAF250a-expression in endometriosis: a biomarker for risk of carcinogenic transformation?

“…Using immunohistochemistry it was demonstrated that ARID1A mutations result in the loss of the protein BRG-associated factor 250a (BAF250a), which is a large subunit of transcriptionregulating Human SWI/SNF complexes and has an important role in the control of cell proliferation and tumor suppression. 7,9,10 Recently, Guan et al 11 found somatic ARID1A mutations in 10/25 uterine endometrioid carcinomas, and could also confirm a strong correlation to loss of BAF250a expression by immunohistochemistry.…”