The role of the SWI/SNF chromatin remodeling complex in maintaining the stemness of glioma initiating cells

Abstract

Glioma initiating cells (GICs) are thought to contribute to therapeutic resistance and tumor recurrence in glioblastoma, a lethal primary brain tumor in adults. Although the stem-like properties of GICs, such as self-renewal and tumorigenicity, are epigenetically regulated, the role of a major chromatin remodeling complex in human, the SWI/SNF complex, remains unknown in these cells. We here demonstrate that the SWI/SNF core complex, that is associated with a unique corepressor complex through the d4-family proteins, DPF1 or DPF3a, plays essential roles in stemness maintenance in GICs. The seruminduced differentiation of GICs downregulated the endogenous expression of DPF1 and DPF3a, and the shRNA-mediated knockdown of each gene reduced both sphere-forming ability and tumor-forming activity in a mouse xenograft model. Rescue experiments revealed that DPF1 has dominant effects over DPF3a. Notably, whereas we have previously reported that d4-family members can function as adaptor proteins between the SWI/SNF complex and NF-κB dimers, this does not significantly contribute to maintaining the stemness properties of GICs. Instead, these proteins were found to link a corepressor complex containing the nuclear receptor, TLX, and LSD1/RCOR2 with the SWI/SNF core complex. Collectively, our results indicate that DPF1 and DPF3a are potential therapeutic targets for glioblastoma.Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults and remains incurable in spite of aggressive treatment approaches. A large body of evidence now indicates that stem-like cells, designated as glioma initiating cells (GICs), are thought to drive GBM propagation and cause therapeutic resistance in these tumors 1-3 . Chromatin structure modification has been shown to be an important determinant of GIC stemness maintenance as well as the induction of their differentiation 4,5 . Recently, using gene expression data from both stem-like and differentiated cell populations, it was shown that the simultaneous expression of four core transcription factors, POU3F2, SALL2, SOX2 and OLIG2, can reprogram differentiated GBM cells into spherogenic stem-like tumor-propagating cells 6 . These results demonstrate a plastic developmental hierarchy in GBM cell populations and reveal essential roles of epigenetic regulation in these biological processes 7 . In humans, the ATP-dependent chromatin remodeling factor, SWI/SNF complex, has been reported to play essential epigenetic roles in many biological processes [8][9][10] . As the catalytic subunit, each SWI/SNF complex has a single molecule of either BRG1 or Brm, but not both. The molecular components of these SWI/SNF complexes are now known to be highly polymorphic, in which some subunits that are encoded by homologous gene family members are integrated into the specific position of the complex in a mutually exclusive manner 8, 9, 11 . Importantly, exchange of a subunit with another family member has often been observed during several developmental processes within either the SWI/SNF core...

Role of Specialized Composition of SWI/SNF Complexes in Prostate Cancer Lineage Plasticity

“…Although the complex is often described as a tumor suppressor role in multiple cancer types 15,24,26,59 , there is also increasing evidence for tumor-promoting functions of SWI/SNF in other malignancies, including leukemia, breast, liver and pancreas cancer, melanoma, glioblastoma, neuroblastoma and synovial sarcoma 25,[60][61][62][63][64][65] . In PCa, the role of SWI/SNF has long remained insufficiently characterized, but our study provides novel evidence that it can have tumor-promoting functions in PCa, including its most aggressive forms.…”

LSD1/KDM1A, a Gate-Keeper of Cancer Stemness and a Promising Therapeutic Target

“…The GSK3β-USP22-LSD1 axis was validated in a cohort of clinical specimens from Grade IV GBM patients, where all three proteins showed increased levels of nuclear expression, significantly higher than their levels in a set of low-grade astrocytomas [98]. In the second study [99] the authors demonstrated that LSD1 participated in a co-repressor complex along with TLX and RCOR2 that was recruited by the SWI/SNF chromatin remodeling complex through the DPF1 and DPF3 adaptors [99]. A series of in vitro and in vivo experiments convincingly showed that this multi-protein complex played a major role in maintaining the stemness and promoting the tumor-initiating capacity of GSCs, probably through the repression of BMP2 and CDKN1A.…”

“…Repression of BMP2 and CDKN1A has been reported to be essential for stemness maintenance of GSCs [96,97]. Two studies uncovered different mechanisms that LSD1 utilized to silence these genes and suppress differentiation [98,99]. In the first study [98] they showed that increased nuclear levels of the β isoform of glycogen synthase kinase 3 (GSK3β) were responsible for the stabilization and accumulation of LSD1 by mediating its phosphorylation, a prerequisite for its binding and subsequent deubiqitination by ubiquitin-specific protease 22 (USP22).…”

Tumor suppression via inhibition of SWI/SNF complex-dependent NF-κB activation

“…We first tested the impact of the knockdown of each d4-family member on anchorage-independent growth using human cancer cell lines originating from non-small cell lung carcinoma (A549) (lacking BRG1 expression) and cervical tumor (HeLaS3) (competent for both BRG1 and Brm expression) using a series of short-hairpin (sh) RNAs 12 , 17 , 20 . All of these shRNAs expressed from lentivirus vectors were previously shown to suppress the corresponding mRNAs at least to 40% of those in cells carrying empty vector.…”