Oncogenesis Caused by Loss of the SNF5 Tumor Suppressor Is Dependent on Activity of BRG1, the ATPase of the SWI/SNF Chromatin Remodeling Complex

Abstract

Alterations in chromatin play an important role in oncogenic transformation, although the underlying mechanisms are often poorly understood. The SWI/SNF complex contributes to epigenetic regulation by using the energy of ATP hydrolysis to remodel chromatin and thus regulate transcription of target genes. SNF5, a core subunit of the SWI/SNF complex, is a potent tumor suppressor that is specifically inactivated in several types of human cancer. However, the mechanism by which SNF5 mutation leads to cancer and the role of SNF5 within the SWI/SNF complex remain largely unknown. It has been hypothesized that oncogenesis in the absence of SNF5 occurs due to a loss of function of the SWI/SNF complex. Here, we show, however, distinct effects for inactivation of Snf5 and the ATPase subunit Brg1 in primary cells. Further, using both human cell lines and mouse models, we show that cancer formation in the absence of SNF5 does not result from SWI/ SNF inactivation but rather that oncogenesis is dependent on continued presence of BRG1. Collectively, our results show that cancer formation in the absence of SNF5 is dependent on the activity of the residual BRG1-containing SWI/SNF complex. These findings suggest that, much like the concept of oncogene addiction, targeted inhibition of SWI/SNF ATPase activity may be an effective therapeutic approach for aggressive SNF5-deficient human tumors.

SMARCB1/INI1 Genetic Inactivation Is Responsible for Tumorigenic Properties of Epithelioid Sarcoma Cell Line VAESBJ

“…However, more recently, engineered mouse models showed that SMARCB1 haploinsufficiency cooperates with both RB and TP53 haploinsufficiency to increase penetrance and reduce latency of tumor onset (9,22,37) and in vitro studies showed that SMARCB1 inactivation globally affects the epigenetic status of the cancer genome (38,39). We observed that VAESBJ cells retain a wild-type TP53 but carry a homozygous deletion of CDKN2A locus, thus displaying impaired p16/RB and p14/TP53 responses.…”

Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers

“…The clinical importance of these findings is highlighted by the prevalence of BRG1 mutations in several cancers, including lung adenocarcinomas. Of note, previous studies have demonstrated that SNF5-deficient malignant rhabdoid tumors are selectively sensitive to BRG1 inhibition (35). Intriguingly, SNF5-deficient malignant rhabdoid tumors lack expression of BRM (35), therefore raising the possibility that this synthetic lethality may, in fact, be explained by the codependency of BRG1 on BRM.…”

ZEB1 represses E-cadherin and induces an EMT by recruiting the SWI/SNF chromatin-remodeling protein BRG1

“…For instance, while BRM expression is frequently lost in tumors affecting the alimentary tract (in particular gastric carcinomas), BRG1 is usually retained (Yamamichi et al, 2007). In fact, BRG1 may act in an oncogenic manner in some tumors (Wang et al, 2009). Furthermore, increased expression of BRG1 has been associated with tumor growth and invasiveness in prostate tumors (Sun et al, 2007) as well as higher metastatic behavior in gastric carcinomas (Sentani et al, 2001).…”