G protein pathway suppressor 2 (GPS2) acts as a tumor suppressor in liposarcoma

Huang, Xiao-Dong; Xiao, Fengjun; Wang, Shaoxia; Yin, Rong‐Hua; Lu, Canrong; Li, Qingfang; Liu, Na; Zhang, Ying; Wang, Lisheng; Li, Peiyu

doi:10.1007/s13277-016-5220-x

Cited by 20 publications

(14 citation statements)

References 35 publications

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“…In this study, we have characterized the role of GPS2 in TNBC cells using a combination of in vitro and in vivo approaches. Overall, our results have confirmed that GPS2 functions as a tumor suppressor, as previously suggested by multiple evidences from genomic profiling of human cancer biopsies and by in vitro data from liposarcoma ( Pugh et al, 2012 ; Huang et al, 2016 ; Priestley et al, 2019 ). Depletion of GPS2 in MDA-MB-231 cells in fact correlates with an increase in proliferation, migration and invasion in vitro , and increased tumor burden with elevated cell proliferation in an in vivo xenograft mouse model of breast cancer.…”

Section: Discussionsupporting

confidence: 88%

“…Emerging evidences indicate that GPS2 downregulation plays an important role in the development of obesity and associated metabolic disorders, through altered regulation of inflammation, mitochondria biogenesis, and lipid metabolism in a variety of cell types, including adipose, liver, and immune cells ( Cardamone et al, 2012 , 2018 ; Toubal et al, 2013 ; Fan et al, 2016 ; Cederquist et al, 2017 ; Drareni et al, 2018 ; Liang et al, 2019 ). GPS2 has also been reported to function as a tumor suppressor in liposarcoma ( Huang et al, 2016 ), in agreement with predictive analyses from genome sequencing data ( Kumar et al, 2015 ). However, a mechanistic understanding of GPS2 role in cancer is currently lacking.…”

Section: Introductionsupporting

confidence: 71%

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Loss of G-Protein Pathway Suppressor 2 Promotes Tumor Growth Through Activation of AKT Signaling

Chan

Smith

Gao

et al. 2021

Front. Cell Dev. Biol.

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G Protein Suppressor 2 (GPS2) is a multifunctional protein that exerts important roles in inflammation and metabolism in adipose, liver, and immune cells. GPS2 has recently been identified as a significantly mutated gene in breast cancer and other malignancies and proposed to work as a putative tumor suppressor. However, molecular mechanisms by which GPS2 prevents cancer development and/or progression are largely unknown. Here, we have profiled the phenotypic changes induced by GPS2 depletion in MDA-MB-231 triple negative breast cancer cells and investigated the underlying molecular mechanisms. We found that GPS2-deleted MDA-MB-231 cells exhibited increased proliferative, migratory, and invasive properties in vitro, and conferred greater tumor burden in vivo in an orthotopic xenograft mouse model. Transcriptomic, proteomic and phospho-proteomic profiling of GPS2-deleted MBA-MB-231 revealed a network of altered signals that relate to cell growth and PI3K/AKT signaling. Overlay of GPS2-regulated gene expression with MDA-MB-231 cells modified to express constitutively active AKT showed significant overlap, suggesting that sustained AKT activation is associated with loss of GPS2. Accordingly, we demonstrate that the pro-oncogenic phenotypes associated with GPS2 deletion are rescued by pharmacological inhibition of AKT with MK2206. Collectively, these observations confirm a tumor suppressor role for GPS2 and reveal that loss of GPS2 promotes breast cancer cell proliferation and tumor growth through uncontrolled activation of AKT signaling. Moreover, our study points to GPS2 as a potential biomarker for a subclass of breast cancers that would be responsive to PI3K-class inhibitor drugs.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionsupporting

confidence: 71%

Loss of G-Protein Pathway Suppressor 2 Promotes Tumor Growth Through Activation of AKT Signaling

Chan

Smith

Gao

et al. 2021

Front. Cell Dev. Biol.

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“…Research uncovered the reduced expression of NCOR in breast and bladder cancers cell lines [84,85] and in vivo experiments showed NCOR function as an oncogene through transcriptional regulation [86]. GPS2 expression was down-regulated in liposarcoma, and depletion of GPS2 in vitro in a liposarcoma cell line increased proliferation and migration [87], suggesting GPS2 to act as a tumor suppressor in liposarcoma. TBL1 was reported as a tumor suppressor gene in pancreatic cancer cells by controlling cell proliferation and invasion [88].…”

Section: The Gps2 Subunit Of the Hdac3 Co-repressor Complexmentioning

confidence: 99%

Loss of the co-repressor GPS2 sensitizes macrophage activation upon metabolic stress induced by obesity and type 2 diabetes

Fan

Toubal

Goñi

et al. 2016

Nat Med

135

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Humans with obesity differ in their susceptibility to developing insulin resistance and type 2 diabetes (T2D). This variation may relate to the extent of adipose tissue (AT) inflammation that develops as their obesity progresses. The state of macrophage activation has a central role in determining the degree of AT inflammation and thus its dysfunction, and these states are driven by epigenomic alterations linked to gene expression. The underlying mechanisms that regulate these alterations, however, are poorly defined. Here we demonstrate that a co-repressor complex containing G protein pathway suppressor 2 (GPS2) crucially controls the macrophage epigenome during activation by metabolic stress. The study of AT from humans with and without obesity revealed correlations between reduced GPS2 expression in macrophages, elevated systemic and AT inflammation, and diabetic status. The causality of this relationship was confirmed by using macrophage-specific Gps2-knockout (KO) mice, in which inappropriate co-repressor complex function caused enhancer activation, pro-inflammatory gene expression and hypersensitivity toward metabolic-stress signals. By contrast, transplantation of GPS2-overexpressing bone marrow into two mouse models of obesity (ob/ob and diet-induced obesity) reduced inflammation and improved insulin sensitivity. Thus, our data reveal a potentially reversible disease mechanism that links co-repressor-dependent epigenomic alterations in macrophages to AT inflammation and the development of T2D.

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“…Liposarcoma is a common type of soft tissue sarcoma that accounts for about 20% [1] of all adult sarcomas. Liposarcoma often develops in deep soft tissues of lower limbs and retroperitoneal parts, accounting for 24% and 45% [2] of limb sarcomas and retroperitoneal soft tissue sarcomas respectively. In accordance with the typical morphological characteristics and biochemical characteristics showed at different stages of adipocyte differentiation, liposarcoma is divided into 3 groups and 5 types by WHO: well-differentiated/ dedifferentiated liposarcoma (WDL/DDL), myxoid/round-cell liposarcoma (MRCL) and pleomorphic liposarcoma (PLS) [3].…”

Section: Introductionmentioning

confidence: 99%

Liposarcoma: Advances in Cellular and Molecular Genetics Alterations and Corresponding Clinical Treatment

Yang¹,

Chen²,

Luo³

et al. 2020

J. Cancer

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Liposarcoma is a malignant tumor of mesenchymal origin with significant tissue diversity. It is composed of adipocytes with different degrees of differentiation and different degrees of heteromorphosis. It is not sensitive to traditional radiotherapy and chemotherapy and has a poor prognosis. In recent years, with the rapid development of basic immunology, molecular genetics and tumor molecular biology, the histological classification of liposarcoma has become increasingly clear. More and more new methods and technologies, such as gene expression profile analysis, the whole genome sequencing, miRNA expression profile analysis and RNA sequencing, have been successfully applied to liposarcoma, bringing about a deeper understanding of gene expression changes and molecular pathogenic mechanisms in the occurrence and development of liposarcoma. This study reviews the present research status and progress of cellular and molecular alterations of liposarcoma and corresponding clinical treatment progress.

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G protein pathway suppressor 2 (GPS2) acts as a tumor suppressor in liposarcoma

Cited by 20 publications

References 35 publications

Loss of G-Protein Pathway Suppressor 2 Promotes Tumor Growth Through Activation of AKT Signaling

Loss of G-Protein Pathway Suppressor 2 Promotes Tumor Growth Through Activation of AKT Signaling

Loss of the co-repressor GPS2 sensitizes macrophage activation upon metabolic stress induced by obesity and type 2 diabetes

Liposarcoma: Advances in Cellular and Molecular Genetics Alterations and Corresponding Clinical Treatment

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