Abstract
BackgroundFAM92A1–289(abbreviated FAM289) is recognized as one of the newly-discovered putative oncogenes. However, its role and molecular mechanisms in promoting cancer progression has not yet been elucidated. This study was performed to reveal its oncogenic functions and molecular mechanisms in human glioblastoma multiforme (GBM) cell models with knockdown or overexpression of FAM289 in vitro and in vivo.MethodsTo elucidate the molecular mechanisms underlying FAM289-mediated tumor progression, the protein-protein interaction between FAM289 and Galectin-1 was verified by co-immunoprecipitation, followed by an analysis of the expression and activity of Galectin-1-associated signaling molecules. Knockdown and overexpression of FAM289 in glioma cells were applied for investigating the effects of FAM289 on cell growth, migration and invasion. The determination of FAM289 expression was performed in specimens from various stages of human gliomas.ResultsFAM289-galectin-1 interaction and concomitant activation of the extracellular signal-regulated kinase (ERK) pathway participated in FAM289-mediated tumor-promoting function. Since the expression of DNA methyl transferase 1 (DNMT1) and DNA methyl transferase 3B (DNMT3B) was regulated by FAM289 in U251 and U87-MG glioma cells, Galectin-1 interaction with FAM289 may promote FAM289 protein into the cell nucleus and activate the ERK pathway, thereby upregulating DNMTs expression. Drug resistance tests indicated that FAM289-mediated TMZ resistance was through stem-like property acquisition by activating the ERK pathway. The correlation between FAM289, Galectin-1 expression and the clinical stage of gliomas was also verified in tissue samples from glioblastoma patients.ConclusionsOur results suggest that high expression of FAM289 in GBM tissues correlated with poor prognosis. FAM289 contributes to tumor progression in malignant glioma by interacting with Galectin-1 thereby promoting FAM289 protein translocation into the cell nucleus. FAM289 in the nucleus activated the ERK pathway, up regulated DNMTs expression and induced stem-like property gene expression which affects drug resistance of glioma cells to TMZ. This study provided functional evidence for FAM289 to be developed as a therapeutic target for cancer treatment.
Highlights
FAM92A1–289(abbreviated FAM289) is recognized as one of the newly-discovered putative oncogenes
We found that the expression of DNA methyl transferase 1 (DNMT1) and DNA methyl transferase 3B (DNMT3B) were regulated by FAM289 in U251 and U87MG glioma cells (Fig. 4C&D)
After treatment with extracellular signal-regulated kinase (ERK) inhibitor U0126, we found that overexpression of FAM289 could counteract the inhibition of pERK and its downstream DNMTS protein expression in U251 cells, while FAM289 knockdown could further promote the inhibition of pERK and its downstream DNMTs protein expression in U87-MG cells (Fig. 4G)
Summary
FAM92A1–289(abbreviated FAM289) is recognized as one of the newly-discovered putative oncogenes. This study was performed to reveal its oncogenic functions and molecular mechanisms in human glioblastoma multiforme (GBM) cell models with knockdown or overexpression of FAM289 in vitro and in vivo. Surgical techniques and adjuvant therapies have undergone progressive development for decades, the therapeutic outcomes for treating GBM remain poor [2]. First and foremost, glioblastoma cells are characterized by a nearly unlimited proliferation capacity, marked resistance to chemotherapeutic agents, as well as fatal dissemination into healthy brain tissue [3,4,5], which are caused by self-renewing properties of cancer stem-like cells (CSCs) [6, 7]. Considering cancer stem-like cell (CSLC) controlled self-renewal as tumor’s ability to survive the therapeutic treatment and reconstitute tumor cellular heterogeneity, it is critical to identify the molecular mechanisms that regulate this activity and discover more efficient therapeutic treatments
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