SMARCC2 mediates the regulation of DKK1 by the transcription factor EGR1 through chromatin remodeling to reduce the proliferative capacity of glioblastoma

Abstract

Switch/sucrose-nonfermenting (SWI/SNF) complexes play a key role in chromatin remodeling. Recent studies have found that SMARCC2, as the core subunit of the fundamental module of the complex, plays a key role in its early assembly. In this study, we found a unique function of SMARCC2 in inhibiting the progression of glioblastoma by targeting the DKK1 signaling axis. Low expression of SMARCC2 is found in malignant glioblastoma (GBM) compared with low-grade gliomas. SMARCC2 knockout promoted the proliferation of glioblastoma cells, while its overexpression showed the opposite effect. Mechanistically, SMARCC2 negatively regulates transcription by dynamically regulating the chromatin structure and closing the promoter region of the target gene DKK1, which can be bound by the transcription factor EGR1. DKK1 knockdown significantly reduced the proliferation of glioblastoma cell lines by inhibiting the PI3K–AKT pathway. We also studied the functions of the SWIRM and SANT domains of SMARCC2 and found that the SWIRM domain plays a more important role in the complete chromatin remodeling function of SMARCC2. In addition, in vivo studies confirmed that overexpression of SMARCC2 could significantly inhibit the size of intracranial gliomas in situ in nude mice. Overall, this study shows that SMARCC2, as a tumor suppressor, inhibits the proliferation of glioblastoma by targeting the transcription of the oncogene DKK1 through chromatin remodeling, indicating that SMARCC2 is a potentially attractive therapeutic target in glioblastoma.

Gene amplification of chromatin remodeling factor SMARCC2 and low protein expression of ACTL6A are unfavorable factors in ovarian high‑grade serous carcinoma

“…Several studies have indicated that SMARCC2 is deficiently expressed in cancer (32,33). SMARCC2 has been reported to inhibit tumor development by mediating the expression of the transcription factor early growth response 1 via chromatin remodeling, and by inhibiting activation of the phosphoinositide 3-kinase-AKT pathway in glioblastoma (33). However, several studies have reported SMARCC2 gene amplification in cancer, such as follicular lymphoma (34) and hepatocellular carcinoma (35), in line with the results of the present study.…”

“…Furthermore, the analysis of TCGA data demonstrated that patients with SMARCC2 amplification had a shorter median OS compared with patients with wild-type SMARCC2 in ovarian serous carcinoma. Several studies have indicated that SMARCC2 is deficiently expressed in cancer (32,33). SMARCC2 has been reported to inhibit tumor development by mediating the expression of the transcription factor early growth response 1 via chromatin remodeling, and by inhibiting activation of the phosphoinositide 3-kinase-AKT pathway in glioblastoma (33).…”

N6-methyladenosine-modified TRIM37 augments sunitinib resistance by promoting the ubiquitin-degradation of SmARCC2 via activating the Wnt signaling pathway in renal cell carcinoma

“…It has been established that SWItch/sucrose non-fermentable (SWI/SNF) is a tumor suppressor that regulates epithelial-mesenchymal transition [26,27]. Moreover, SMARCC2 is the core subunit of the SWI/SNF complex[28], which is prone to mutation in various malignant cancers, resulting in low expression levels [29,30]. Our investigation unveiled SMARCC2 as a potential interacting partner of TRIM37 through CO-IP assays and mass spectrometry.…”

SUMOylation of RALY promotes vasculogenic mimicry in glioma cells via the FOXD1/DKK1 pathway

“…Furthermore, studies have revealed that elevated levels of DKK1 are linked to the poor prognosis of gliomas. Knockdown of DKK1 significantly reduced cell proliferation by inhibiting the PI3K-AKT pathway in glioma (Li et al 2022 ). However, an in-depth mechanism of the functional role of FOXD1 and DKK1 in glioma VM remains unknown.…”