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Nuclear FAM289-Galectin-1 interaction controls FAM289-mediated tumor promotion in malignant glioma
Xing Rong Guo1,2, Mu Yu Wu3,4, Long Jun Dai5,6
1Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China. 4178206@qq.com.
Background:
FAM92A1-289(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.
Methods:
To 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.
Results:
FAM289-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.
Conclusions:
Our 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.
Insights
This study reveals that high FAM289 expression drives glioblastoma progression by interacting with Galectin-1, activating the ERK pathway, and increasing drug resistance. FAM289 is a potential therapeutic target for malignant glioma.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- FAM92A1-289 (FAM289) is a newly identified putative oncogene.
- Its role in cancer progression and molecular mechanisms remain largely unknown.
- This study investigates FAM289's function in human glioblastoma multiforme (GBM).
Purpose of the Study:
- To elucidate the oncogenic functions and molecular mechanisms of FAM289 in glioblastoma.
- To investigate the interaction between FAM289 and Galectin-1.
- To determine the effect of FAM289 on glioma cell behavior and drug resistance.
Main Methods:
- Co-immunoprecipitation to verify FAM289-Galectin-1 interaction.
- Analysis of Galectin-1 signaling pathway components.
- FAM289 knockdown and overexpression in glioma cells (in vitro and in vivo).
- Assessment of cell growth, migration, invasion, and drug resistance (TMZ).
- Determination of FAM289 expression in human glioma specimens.
Main Results:
- FAM289 interacts with Galectin-1, activating the ERK pathway and promoting tumor progression.
- FAM289 upregulates DNA methyltransferases (DNMT1 and DNMT3B) via nuclear translocation and ERK activation.
- FAM289 confers TMZ resistance by inducing stem-like properties through ERK pathway activation.
- High FAM289 and Galectin-1 expression correlates with advanced glioma stages.
Conclusions:
- FAM289 overexpression in GBM correlates with poor prognosis.
- FAM289 promotes glioma progression via Galectin-1 interaction, nuclear translocation, and ERK pathway activation.
- FAM289 induces stem-like properties, contributing to TMZ resistance.
- FAM289 represents a promising therapeutic target for malignant gliomas.
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