OTUB2 stabilizes U2AF2 to promote the Warburg effect and tumorigenesis via the AKT/mTOR signaling pathway in non-small cell lung cancer

Li, Jing; Cheng, Dongdong; Zhu, Ming; Yu, Huajian; Pan, Zhifang; Liu, Lei; Geng, Qin; Pan, Hongyu; Yan, Mingxia; Yao, Ming

doi:10.7150/thno.29545

Cited by 99 publications

(82 citation statements)

References 64 publications

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“…Consistently, we found in NFPTs a downregulation of U2AF2, an SF that heterodimerizes with U2AF1. Although the relationship of U2AF2 with tumorigenesis is poorly studied, certain reports have demonstrated cancer-associated mutations in this SF [54], and it has also been found upregulated in lung cancer and highly metastatic hepatocellular carcinoma [55]. Remarkably, we found that SRRM4 was the only SF significantly upregulated in NFPTs, which was also associated with higher chiasmatic compression.…”

Section: Discussionsupporting

confidence: 59%

Splicing Machinery is Dysregulated in Pituitary Neuroendocrine Tumors and is Associated with Aggressiveness Features

Vázquez-Borrego

Fuentes-Fayos

Venegas-Moreno

et al. 2019

Cancers

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Pituitary neuroendocrine tumors (PitNETs) constitute approximately 15% of all brain tumors, and most have a sporadic origin. Recent studies suggest that altered alternative splicing and, consequently, appearance of aberrant splicing variants, is a common feature of most tumor pathologies. Moreover, spliceosome is considered an attractive therapeutic target in tumor pathologies, and the inhibition of SF3B1 (e.g., using pladienolide-B) has been shown to exert antitumor effects. Therefore, we aimed to analyze the expression levels of selected splicing-machinery components in 261 PitNETs (somatotropinomas/non-functioning PitNETS/corticotropinomas/prolactinomas) and evaluated the direct effects of pladienolide-B in cell proliferation/viability/hormone secretion in human PitNETs cell cultures and pituitary cell lines (AtT-20/GH3). Results revealed a severe dysregulation of splicing-machinery components in all the PitNET subtypes compared to normal pituitaries and a unique fingerprint of splicing-machinery components that accurately discriminate between normal and tumor tissue in each PitNET subtype. Moreover, expression of specific components was associated with key clinical parameters. Interestingly, certain components were commonly dysregulated throughout all PitNET subtypes. Finally, pladienolide-B reduced cell proliferation/viability/hormone secretion in PitNET cell cultures and cell lines. Altogether, our data demonstrate a drastic dysregulation of the splicing-machinery in PitNETs that might be associated to their tumorigenesis, paving the way to explore the use of specific splicing-machinery components as novel diagnostic/prognostic and therapeutic targets in PitNETs.

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Section: Discussionsupporting

confidence: 59%

Splicing Machinery is Dysregulated in Pituitary Neuroendocrine Tumors and is Associated with Aggressiveness Features

Vázquez-Borrego

Fuentes-Fayos

Venegas-Moreno

et al. 2019

Cancers

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“…Bioinformatics analysis suggested that U2AF2 was upregulated in IDH-mutated glioma with malignant transformation [46]. U2AF2 expression was significantly upregulated in primary non-small cell lung cancer and was associated with metastasis, advanced tumor stages, poor survival, and recurrence [47]. In addition, U2AF2 is significantly increased in melanoma progression and participates in brain metastasis [48].…”

Section: Discussionmentioning

confidence: 99%

The U2AF2 /circRNA ARF1/miR-342–3p/ISL2 feedback loop regulates angiogenesis in glioma stem cells

Jiang

Zhou

Zhao

et al. 2020

J Exp Clin Cancer Res

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Background Glioma is the most common and lethal primary brain tumor in adults, and angiogenesis is one of the key factors contributing to its proliferation, aggressiveness, and malignant transformation. However, the discovery of novel oncogenes and the study of its molecular regulating mechanism based on circular RNAs (circRNAs) may provide a promising treatment target in glioma. Methods Bioinformatics analysis, qPCR, western blotting, and immunohistochemistry were used to detect the expression levels of ISL2, miR-342–3p, circRNA ARF1 (cARF1), U2AF2, and VEGFA. Patient-derived glioma stem cells (GSCs) were established for the molecular experiments. Lentiviral-based infection was used to regulate the expression of these molecules in GSCs. The MTS, EDU, Transwell, and tube formation assays were used to detect the proliferation, invasion, and angiogenesis of human brain microvessel endothelial cells (hBMECs). RNA-binding protein immunoprecipitation, RNA pull-down, dual-luciferase reporter, and chromatin immunoprecipitation assays were used to detect the direct regulation mechanisms among these molecules. Results We first identified a novel transcription factor related to neural development. ISL2 was overexpressed in glioma and correlated with poor patient survival. ISL2 transcriptionally regulated VEGFA expression in GSCs and promoted the proliferation, invasion, and angiogenesis of hBMECs via VEGFA-mediated ERK signaling. Regarding its mechanism of action, cARF1 upregulated ISL2 expression in GSCs via miR-342–3p sponging. Furthermore, U2AF2 bound to and promoted the stability and expression of cARF1, while ISL2 induced the expression of U2AF2, which formed a feedback loop in GSCs. We also showed that both U2AF2 and cARF1 had an oncogenic effect, were overexpressed in glioma, and correlated with poor patient survival. Conclusions Our study identified a novel feedback loop among U2AF2, cARF1, miR-342–3p, and ISL2 in GSCs. This feedback loop promoted glioma angiogenesis, and could provide an effective biomarker for glioma diagnosis and prognostic evaluation, as well as possibly being used for targeted therapy.

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“…PKM2 has been reported to be upregulated in tumor cells and cancer stem cells, playing a role in glycolysis and tumor malignancy (7). Furthermore, a number of previous studies have indicated that glycolysis is closely related to cell proliferation and metastasis in nSclc (8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Long non‑coding RNA BCYRN1 promotes glycolysis and tumor progression by regulating the miR‑149/PKM2 axis in non‑small‑cell lung cancer

et al. 2020

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cancer cells use aerobic glycolysis to sustain their proliferation. long non-coding rna brain cytoplasmic rna 1 (BcYrn1) has been reported to act as an oncogene in non-small-cell lung cancer (nSclc). The present study investigated the role of BcYrn1 in nSclc glycolysis. BcYrn1 expression was detected in nSclc cells and tissues using reverse transcription-quantitative Pcr. The effect of BcYrn1 on aerobic glycolysis was examined by measuring nSclc cell glucose catabolism and lactate synthesis. The relationships between BcYrn1 and microrna (mir)-149, and between mir-149 and pyruvate kinase M1/2 (PKM2) were measured using a dual-luciferase reporter assay. cell proliferation and invasion were analyzed by the cell counting kit-8 assay and the Matrigel invasion assay, respectively. High BcYrn1 expression was observed in nSclc tissues and cells compared with the corresponding controls. BcYrn1 induced glycolysis and upregulated the expression levels of PKM2 in nSclc cells. in addition, BcYrn1 regulated mir-149 expression levels, and mir-149 inhibitor rescued the effects of si-BcYrn1 on glucose consumption and lactate production. miR-149 knockdown significantly enhanced the expression of PKM2. Furthermore, PKM2 inhibition significantly reversed the effects of mir-149 inhibitor on glucose catabolism and lactate synthesis. Furthermore, PKM2 was involved in nSclc cell proliferation and invasion, and BcYrn1 knockdown and mir-149 overexpression inhibited both processes. The present study suggested that BcYrn1 was involved in cell glycolysis, proliferation and invasion during nSclc via regulating mir-149 and PKM2.

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OTUB2 stabilizes U2AF2 to promote the Warburg effect and tumorigenesis via the AKT/mTOR signaling pathway in non-small cell lung cancer

Cited by 99 publications

References 64 publications

Splicing Machinery is Dysregulated in Pituitary Neuroendocrine Tumors and is Associated with Aggressiveness Features

Splicing Machinery is Dysregulated in Pituitary Neuroendocrine Tumors and is Associated with Aggressiveness Features

The U2AF2 /circRNA ARF1/miR-342–3p/ISL2 feedback loop regulates angiogenesis in glioma stem cells

Long non‑coding RNA BCYRN1 promotes glycolysis and tumor progression by regulating the miR‑149/PKM2 axis in non‑small‑cell lung cancer

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