Analysis of cellular and molecular antitumor effects upon inhibition of SATB1 in glioblastoma cells

Abstract

BackgroundThe Special AT-rich Sequence Binding Protein 1 (SATB1) regulates the expression of many genes by acting as a global chromatin organizer. While in many tumor entities SATB1 overexpression has been observed and connected to pro-tumorigenic processes, somewhat contradictory evidence exists in brain tumors with regard to SATB1 overexpression in glioblastoma and its association with poorer prognosis and tumor progression. On the functional side, initial data indicate that SATB1 may be involved in several tumor cell-relevant processes.MethodsFor the detailed analysis of the functional relevance and possible therapeutic potential of SATB1 inhibition, we employ transient siRNA-mediated knockdown and comprehensively analyze the cellular and molecular role of SATB1 in glioblastoma.ResultsIn various cell lines with different SATB1 expression levels, a SATB1 gene dose-dependent inhibition of anchorage-dependent and –independent proliferation is observed. This is due to cell cycle-inhibitory and pro-apoptotic effects of SATB1 knockdown. Molecular analyses reveal SATB1 knockdown effects on multiple important (proto-) oncogenes, including Myc, Bcl-2, Pim-1, EGFR, β-catenin and Survivin. Molecules involved in cell cycle, EMT and cell adhesion are affected as well. The putative therapeutic relevance of SATB1 inhibition is further supported in an in vivo tumor xenograft mouse model, where the treatment with polymeric nanoparticles containing SATB1-specific siRNAs exerts antitumor effects.ConclusionOur results demonstrate that SATB1 may represent a promising target molecule in glioblastoma therapy whose inhibition or knockdown affects multiple crucial pathways.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-3006-6) contains supplementary material, which is available to authorized users.

Lactate dehydrogenase is correlated with clinical stage and grade and is downregulated by si‑STAB1 in ovarian cancer

“…In the present study, we revealed that SATB1, a nuclear architectural protein that organizes chromatin structure (31,32), plays an important role in reprogramming the energy metabolism of ovarian cancer cells by regulating the expression levels of LDH and MCT1. The present findings demonstrated that stable knockdown of SATB1 expression using siRNA inhibited ovarian cancer cell proliferation by downregulating both LDH and MCT1 expression.…”

Cytokine Networks and Survivin Peptide-Specific Cellular Immune Responses Predict Improved Survival in Patients With Glioblastoma Multiforme

“…Encoded by the BIRC5 gene, survivin is an anti-apoptotic protein which associates with caspase-9 to inhibit the intrinsic apoptotic pathway, while promoting mitosis in cells; its overexpression in cancer cells perpetrates uncontrolled proliferation leading to disease progression [ 35 , 36 ]. Downregulation of survivin expression in glioblastoma cell lines (G55T2 and U-87 MG) via siRNA-based knockdown of the Special AT-rich Sequence-Binding Protein 1 (SATB1) regulator has been shown to induce apoptosis and cell growth arrest [ 37 ]. Furthermore, the survivin-based conjugate vaccine SurVaxM was recently tested in a phase I clinical trial involving patients with GBM (NCT02455557), while IMA950, a multi-peptide conjugate vaccine candidate also incorporating the survivin peptide TLGEFLKLDRERAKN, showed promising immunogenicity in patients with GBM, which is currently in phase II clinical trials (NCT01920191) for HLA-A*02+ individuals [ 38 ].…”

Functional relevance of SATB1 in immune regulation and tumorigenesis

“…Since the discovery of SATB1, its role in the pathogenesis of various cancers has been investigated. Importantly, upregulation of SATB1 has been shown to promote many pathological features across a wide range of cancers [38,39] including breast [1,[40][41][42], colorectal [2,[43][44][45], lung [46,47], nasopharyngeal [48], oesophageal [3,49,50], gastric [51,52], pancreatic [53,54], ovarian [32,55,56], liver [57][58][59], prostate [60][61][62][63], bladder [64,65], and brain [66][67][68][69][70]. In most cancers, the SATB1 expression is positively associated with increased tumour size, lymph node involvement and metastasis [71,72], tumour progression [1,2], poor prognosis [50,56] and reduced overall survival [49,54].…”

“…These studies clearly demonstrate that the dysregulation of SATB1 in cancer leads to an altered immune response, which can promote tumorigenesis and tumour progression. epidermal growth factor receptor (EGFR), β-catenin and Survivin [66]. In pancreatic cancer cells, SATB1 was found to be overexpressed and positively regulated the proto-oncogene MYC [53].…”