The reversible epigenetic silencing of BRM: implications for clinical targeted therapy

Abstract

The SWI/SNF chromatin-remodeling complex serves as a master switch that directs and limits the execution of specific cellular programs, such as differentiation and growth control. SWI/SNF function requires one of two paralogous ATPase subunits, Brahma (BRM) or BRMrelated gene 1 (BRG1), which we previously found are lost together in cancer cell lines and primary lung cancers. Although BRG1 has been found to be mutated in cancer cell lines, the mechanisms underlying BRM silencing are not known. To address this question, we sequenced BRM in 10 BRM/BRG1-deficient cancer cell lines and found that BRM was devoid of abrogating mutations. Moreover, histone deacetylase (HDAC) inhibitors restored BRM expression in each of these BRG1/BRM-deficient cancer cell lines, indicating that epigenetic silencing is a major mechanism underlying the loss of BRM expression. Despite their ability to restore BRM expression, these HDAC inhibitors also blocked BRM function when present. However, after their removal, we observed that BRM expression remained elevated for several days, and during this period, BRM activity was detected. We also found that the suppression of BRM occurs in a broad range of human tumor types and that loss of one or both BRM alleles potentiated tumor development in mice. Thus, BRG1 and BRM are silenced by different mechanisms, and it may be possible to clinically target and reexpress BRM in a number of tumor types, potentially impacting tumor development.

SWI/SNF-Mediated Lineage Determination in Mesenchymal Stem Cells Confers Resistance to Osteoporosis

“…BRM is epigenetically silenced in a wide range of tumors 30, 31, and BRM‐null mice are sensitive to carcinogen‐induced tumors 41, 42, but the mice do not show increased spontaneous susceptibility to cancer 6, 30, 31, and BRM has actually been identified as a target for cancer treatment, discussed further below. Developmental changes linked with BRM insufficiency are surprisingly few.…”

The SWI/SNF complex and cancer

“…Sequence analysis of BRM from 10 BRM-deficient cell lines did not reveal any mutations or other alterations that could explain why BRM is silenced (Glaros et al, 2007). Unlike BRG1, experimental analysis by various groups has revealed that BRM is epigenetically silenced in 17 out of the 17 cell lines examined (Mizutani et al, 2002;Bourachot et al, 2003;Yamamichi et al, 2005;Glaros et al, 2007).…”

“…Instead, in adult tumors, the major cancer defect in SWI/SNF appears to be the loss of BRG1, BRM or both (Muchardt and Yaniv, 2001). This appears to occur between 10 and 20% of a variety of tumor types (Reisman et al, 2003;Glaros et al, 2007).…”

“…Unlike BRG1, experimental analysis by various groups has revealed that BRM is epigenetically silenced in 17 out of the 17 cell lines examined (Mizutani et al, 2002;Bourachot et al, 2003;Yamamichi et al, 2005;Glaros et al, 2007). The observation that BRM is epigenetically silenced in cancer, rather than mutated, suggests that it might be possible to restore BRM function in tumor cells.…”

“…Given that BRM is lost in B20% of a broad range of human cancers (Glaros et al, 2007), and that the introduction of BRM into BRM-deficient cell lines causes growth arrest Muchardt and Yaniv, 1999b;Bourachot et al, 2003), it is plausible that restoration of BRM expression might be clinically desirable. Several groups, including our own, have observed that histone deacetylase (HDAC) inhibitors can restore BRM mRNA and protein expression in a variety of BRM null cell lines (Mizutani et al, 2002;Bourachot et al, 2003;Yamamichi et al, 2005;Glaros et al, 2007). Nuclear run-on transcription assays were used by Yamamichi et al (2005) to show that BRM is strongly suppressed at the post-transcriptional level and that this suppression could be reversed by HDAC inhibitor treatment.…”