Nuclear PTEN safeguards pre-mRNA splicing to link Golgi apparatus for its tumor suppressive role

Shen, Shao‐Ming; Ji, Yan; Zhang, Cheng; Dong, Shuang-Shu; Yang, Shuo; Xiong, Zhong; Ge, Meng-Kai; Yu, Yun; Li, Xia; Guo, Meng; Cheng, Jinke; Liu, Junling; Yu, Jianxiu; Chen, Guoqiang

doi:10.1038/s41467-018-04760-1

Cited by 50 publications

(42 citation statements)

References 67 publications

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“…4e). Previously, we reported that nuclear PTEN regulates the efficiency of alternative splicing of cancerrelated genes, including GOLGA2, whose splicing promotes Golgi extension and secretion 20 . We thus tested whether FBXO22 also plays a role in alternative splicing.…”

Section: Resultsmentioning

confidence: 99%

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FBXO22 degrades nuclear PTEN to promote tumorigenesis

Zhang

et al. 2020

Nat Commun

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Nuclear localization of PTEN is essential for its tumor suppressive role, and loss of nuclear PTEN is more prominent than cytoplasmic PTEN in many kinds of cancers. However, nuclear PTEN-specific regulatory mechanisms were rarely reported. Based on the finding that nuclear PTEN is more unstable than cytoplasmic PTEN, here we identify that F-box only protein 22 (FBXO22) induces ubiquitylation of nuclear but not cytoplasmic PTEN at lysine 221, which is responsible for the degradation of nuclear PTEN. FBXO22 plays a tumor-promoting role by ubiquitylating and degrading nuclear PTEN. In accordance, FBXO22 is overexpressed in various cancer types, and contributes to nuclear PTEN downregulation in colorectal cancer tissues. Cumulatively, our study reports the mechanism to specifically regulate the stability of nuclear PTEN, which would provide the opportunity for developing therapeutic strategies aiming to achieve complete reactivation of PTEN as a tumor suppressor.

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Section: Resultsmentioning

confidence: 99%

“…During the last decade, the tumor suppressive role of nuclear PTEN has been supported by the discovery of a variety of functions exerted by the nuclear PTEN, mostly independent of its lipid phosphatase activity 10,14,19,20,22 . Despite its importance, the property of nuclear PTEN remains largely unknown.…”

Section: Discussionmentioning

confidence: 99%

FBXO22 degrades nuclear PTEN to promote tumorigenesis

Zhang

et al. 2020

Nat Commun

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“…What is clearer than whether ASEs are, in part, a cause or an effect or aspects of PTEN-ASD is the role of Pten in the regulation of AS. Previous work has shown that PTEN interacts with several splicing factors, notably many members of the hnRNP splicing factor family 18 , 24 . Moreover, it is well understood that several kinase-activated signaling cascades, of which PTEN is a critical antagonist, regulate the phosphorylation status of splicing factors, especially those belonging to the SR-protein family 25 .…”

Section: Discussionmentioning

confidence: 99%

“…Generally, the Pten m3m4 neural transcriptome mimicked that of idiopathic ASD, demonstrating an increase in expression of markers of inflammation and a decrease in markers of synaptic transmission 14 . Considering the association of PTEN with ASD and even more recently with the regulation AS 18 , we hypothesized that the neural transcriptome of the Pten m3m4 mouse will show differential patterns of AS and that these patterns will associate with pathophysiological hallmarks of ASD.…”

Section: Introductionmentioning

confidence: 99%

Alternative splicing landscape of the neural transcriptome in a cytoplasmic-predominant Pten expression murine model of autism-like Behavior

2020

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Alternative splicing (AS) is a posttranscriptional mechanism regulating gene expression that complex organisms utilize to expand proteome diversity from a comparatively limited set of genes. Recent research has increasingly associated AS with increased functional complexity in the central nervous systems in higher order mammals. This work has heavily implicated aberrant AS in several neurocognitive and neurodevelopmental disorders, including autism. Due to the strong genetic association between germline PTEN mutations and autism spectrum disorder (ASD), we hypothesized that germline PTEN mutations would alter AS patterns, contributing to the pathophysiology of ASD. In a murine model of constitutional mislocalization of Pten, recapitulating an autism-like phenotype, we found significant changes in AS patterns across the neural transcriptome by analyzing RNA-sequencing data with the program rMATS. A few hundred significant alternative splicing events (ASEs) that differentiate each m3m4 genotype were identified. These ASEs occur in genes enriched in PTEN signaling, inositol metabolism, and several other pathways relevant to the pathophysiology of ASD. In addition, we identified expression changes in several splicing factors known to be enriched in the nervous system. For instance, the master regulator of microexons, Srrm4, has decreased expression, and consequently, we found decreased inclusion of microexons in the Ptenm3m4/m3m4 cortex (~10% decrease). We also demonstrated that the m3m4 mutation disrupts the interaction between Pten and U2af2, a member of the spliceosome. In sum, our observations point to germline Pten disruption changing the landscape of alternative splicing in the brain, and these changes may be relevant to the pathogenesis and/or maintenance of PTEN-ASD phenotypes.

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“…In addition, classic tumour suppressor phosphatase and tensin homologue could affect proteins on the Golgi apparatus to play a role in tumour suppression by interacting with spliceosome [36]. However, no relevant study related to GOLGA8B and spliceosome was found.…”

Section: Discussionmentioning

confidence: 99%

Clinical Value and Potential Mechanisms Exploration of GOLGA8B in Hepatocellular Carcinoma: A Comprehensive Investigation Based on Real-Time Quantitative Polymerase Chain Reaction, RNA-seq, Microarray and Immunohistochemistry

Ma¹,

Zhai²,

Wu³

et al. 2019

Preprint

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Introduction Recent studies found that GOLGA8B plays an essential role in different cancers. However, the role GOLGA8B plays in the carcinogenesis and development of hepatocellular carcinoma (HCC) remains unclear. This study explores the clinical significance and prospective mechanisms of GOLGA8B in HCC. Materials and methods The expression of GOLGA8B was detected in tissues of HCC and non-HCC controls. A real-time quantitative polymerase chain reaction analysis was performed to evaluate the mRNA expression of GOLGA8B. RNA-sequencing data and microarray chip data were obtained for further analysis. The role GOLGA8B plays in patients with HCC was also evaluated. An immunohistochemistry (IHC) analysis was also performed to evaluate the protein expression of GOLGA8B. The different GOLGA8B expression resources, including mRNA and protein expression, were integrated by calculating standard mean difference (SMD) and summary of the receiver operator characteristic (sROC). Genes co-expressed GOLGA8B were predicted. Enrichment analyses including Gene ontology (GO) and biological pathway were performed to investigate the essential molecular mechanisms. Hub genes were screened out by a protein-protein interactions network. MicroRNAs which target GOLGA8B at a posttranscriptional level were also predicted. Results According to different resources, GOLGA8B manifested a higher expression in tissues of HCC than in non-HCC controls and exhibited clinical values for HCC. The RT-qPCR analysis revealed an increasing trend of GOLGA8B expression in HCC. GOLGA8B expresssion was significantly increased in RNA-sequencing and 7 of 13 microarray chip. IHC analysis also revealed significantly higher expression of GOLGA8B protein. Moreover, GOLGA8B expression was correlated with pathologic tumors and stages according to RNA-sequencing data and IHC analysis. The integrated SMD and sROC of different resources was 0.893 (P=0.004) and 0.79. A total 1303 co-expressed genes were gathered to perform enrichment analyses. The most significant biological pathways of co-expressed genes were spliceosome and mitogen-activated protein kinase signalling (MAPK). Four hub genes (SF3B1, HNRNPA2B1, HNRNPA1 and SRRM2) and five miRNAs (miR-369-3p, miR-203a, miR-374b-5p, miR-139-5p and miR-144-3p) were screened out. Conclusion GOLGA8B expression was increased in HCC and may serve as a novel target for HCC diagnosis and treatment.

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Nuclear PTEN safeguards pre-mRNA splicing to link Golgi apparatus for its tumor suppressive role

Cited by 50 publications

References 67 publications

FBXO22 degrades nuclear PTEN to promote tumorigenesis

FBXO22 degrades nuclear PTEN to promote tumorigenesis

Alternative splicing landscape of the neural transcriptome in a cytoplasmic-predominant Pten expression murine model of autism-like Behavior

Clinical Value and Potential Mechanisms Exploration of GOLGA8B in Hepatocellular Carcinoma: A Comprehensive Investigation Based on Real-Time Quantitative Polymerase Chain Reaction, RNA-seq, Microarray and Immunohistochemistry

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