Alternative Splicing of the Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT) Is Regulated by RBFOX2 in Lymphoid Malignancies

Cooper, Amy M.; Nutter, Curtis A.; Kuyumcu‐Martinez, Muge N.; Wright, Casey W.

doi:10.1128/mcb.00503-21

“…The mRNA level of RBFOX2 was significantly upregulated in nasopharyngeal carcinoma (NPC) tissues, correlating with the initiation of NPC cell tumorigenesis (Luo et al, 2021). Suppression of RBFOX2 significantly decreased the growth and survival of lymphoid malignancies by regulating aberrant alternative splicing of ARNT (Cooper et al, 2022), which was consistent in this study that RBFOX2 was high in DLBC tissues. Knockdown of RBFOX2 significantly upregulation of the KIF1B and increased sensitivity to anoikis in ovarian cancer cells (Gordon et al, 2019).…”

Section: Discussionsupporting

confidence: 87%

Integrated pan-cancer analysis reveals the immunological and prognostic potential of RBFOX2 in human tumors

Huang,

Jin,

Zhang

et al. 2024

Front. Pharmacol.

1

0

View full text Add to dashboard Cite

BackgroundThe role of RNA-binding fox one homolog 2 (RBFOX2) in the progression of multiple tumors is increasingly supported by evidence. However, the unclearness pertaining to the expression of RBFOX2, its prognostic potential, and its correlation with the tumor microenvironment (TME) in pan-cancer persists. This study aims to comprehensively investigate the immunological prognostic value of RBFOX2.MethodsThe Cancer Genome Atlas Gene Expression Omnibus Genotype-Tissue Expression (GTEx), TIMER2.0, Kaplan-Meier (K–M) Plotter, University of Alabama at Birmingham Cancer data analysis Portal (UALCAN), cbioportal, and Gene Expression Profiling Interactive Analysis 2 (GEPIA2) were utilized for a systematic analysis of RBFOX2. This analysis included studying its expression, prognostic value, DNA methylation, enrichment analysis, immune infiltration cells, and immune-related genes. Additionally, qRT-PCR, CCK-8, colony formation, transwell assays, and immunohistochemistry were employed to analyze the expression and biological function of RBFOX2 in liver cancer.ResultsVariations in RBFOX2 expression have been observed across diverse tumors and have been identified as indicators of unfavorable prognosis. It is closely linked to immune infiltration cells, immune checkpoints, chemokines, and chemokine receptors in the TME. Higher levels of RBFOX2 have been significantly associated with low response and poor prognosis in patients with non-small cell lung cancer (NSCLC) and melanoma who receive immunotherapy. Furthermore, the DNA methylation of RBFOX2 varies across different types of cancer and has shown better prognosis in patients with BLCA, BRCA, CESC, COAD, DLBC, HNSC, LAML, LGG, LUAD, PAAD, SKCM and THYM. Interestingly, RBFOX2 expression was found to be lower in hepatocellular carcinoma (HCC) patients’ tumor tissues compared to their paired adjacent tissues. In vitro studies have shown that knockdown of RBFOX2 significantly promotes the growth and metastasis of liver cancer cells.ConclusionThis study investigates the correlation between DNA methylation, prognostic value, and immune cell infiltration with the expression of RBFOX2 in pan-cancer and indicates its potential role to inhibit metastasis of liver cancer.

show abstract

“…ARNT promotes organogenesis and neural development (52). Ectopic expression of ARNT leads to attenuated physiological adaptation to hypoxia and pollutants, and promotes the initiation and progression of cancerous cells (52,53). Accumulating evidence reveals that ARNT is upregulated in a variety of cancer tissues and cell lines, indicating the involvement of ARNT in tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Targeting ARNT attenuates Chemoresistance Through Destabilizing p38α-MAPK Signaling in Glioblastoma

Alafate,

Lv,

Zheng

et al. 2024

Preprint

0

View full text Add to dashboard Cite

Glioblastoma (GBM) is the most aggressive and lethal brain tumor in adults. This study aimed to investigate the functional significance of aryl hydrocarbon receptor nuclear translocator (ARNT) in the pathogenesis of GBM. Analysis of public datasets revealed ARNT is upregulated in GBM tissues compared to lower grade gliomas or normal brain tissues. Higher ARNT expression correlated with the mesenchymal subtype and poorer survival in GBM patients. Silencing ARNT using lentiviral shRNAs attenuated the proliferative, invasive, and stem-like capabilities of GBM cell lines, while ARNT overexpression enhanced these malignant phenotypes. Single-cell RNA sequencing uncovered that ARNT is highly expressed in a stem-like subpopulation and is involved in regulating glycolysis, hypoxia response, and stress pathways. Mechanistic studies found ARNT activates p38 mitogen-activated protein kinase (MAPK) signaling to promote chemoresistance in GBM cells. Disrupting the ARNT/p38α protein interaction via the ARNT PAS-A domain restored temozolomide sensitivity. Overall, this study demonstrates ARNT functions as an oncogenic driver in GBM pathogenesis and represents a promising therapeutic target.

show abstract

“…ARNT promotes organogenesis and neural development [ 54 ]. Ectopic expression of ARNT leads to attenuated physiological adaptation to hypoxia and pollutants, and promotes the initiation and progression of cancerous cells [ 54 , 55 ]. Accumulating evidence reveals that ARNT is upregulated in a variety of cancer tissues and cell lines, indicating the involvement of ARNT in tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Targeting ARNT attenuates chemoresistance through destabilizing p38α-MAPK signaling in glioblastoma

Alafate,

Lv,

Zheng

et al. 2024

Cell Death Dis

1

0

View full text Add to dashboard Cite

Glioblastoma (GBM) is the most aggressive and lethal brain tumor in adults. This study aimed to investigate the functional significance of aryl hydrocarbon receptor nuclear translocator (ARNT) in the pathogenesis of GBM. Analysis of public datasets revealed ARNT is upregulated in GBM tissues compared to lower grade gliomas or normal brain tissues. Higher ARNT expression correlated with the mesenchymal subtype and poorer survival in GBM patients. Silencing ARNT using lentiviral shRNAs attenuated the proliferative, invasive, and stem-like capabilities of GBM cell lines, while ARNT overexpression enhanced these malignant phenotypes. Single-cell RNA sequencing uncovered that ARNT is highly expressed in a stem-like subpopulation and is involved in regulating glycolysis, hypoxia response, and stress pathways. Mechanistic studies found ARNT activates p38 mitogen-activated protein kinase (MAPK) signaling to promote chemoresistance in GBM cells. Disrupting the ARNT/p38α protein interaction via the ARNT PAS-A domain restored temozolomide sensitivity. Overall, this study demonstrates ARNT functions as an oncogenic driver in GBM pathogenesis and represents a promising therapeutic target.

show abstract

Alternative Splicing of the Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT) Is Regulated by RBFOX2 in Lymphoid Malignancies

Cited by 8 publications

References 40 publications

Integrated pan-cancer analysis reveals the immunological and prognostic potential of RBFOX2 in human tumors

Integrated pan-cancer analysis reveals the immunological and prognostic potential of RBFOX2 in human tumors

Targeting ARNT attenuates Chemoresistance Through Destabilizing p38α-MAPK Signaling in Glioblastoma

Targeting ARNT attenuates chemoresistance through destabilizing p38α-MAPK signaling in glioblastoma

Contact Info

Product

Resources

About