PTBP1 promotes hepatocellular carcinoma progression by regulating the skipping of exon 9 in NUMB pre-mRNA

He, Zhentao; Ni, Q.; Li, Xichun; Zhao, Mingyu; Mo, Qingguo; Duo, Yongsheng

doi:10.1016/j.heliyon.2023.e17387

Cited by 2 publications

(2 citation statements)

References 32 publications

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“…Furthermore, Numb exon 9 inclusion is increased in multiple cancers including all breast cancer subtypes. This is of particular interest given that isoforms including exon 9 promote proliferation which can contribute to cancer progression [30,41,52,53]. Similarly, mutations in the splicing factor RBM10 lead to increased exon 9 inclusion in Numb which promotes lung cancer cell growth [35].…”

Section: Discussionmentioning

confidence: 99%

“…To test the hypothesis that the mechanical control of the subcellular localisation of PTBP1 results in mechanically controlled splicing events, we investigated if the splicing of the wellestablished PTBP1 splicing target Numb depends on mechanical cues [30,31]. Numb is an adapter protein that displays multiple functions, which include the regulation of cell fate choice [32], endocytosis [33,34], and proliferation [35,36].…”

Section: Ptbp1 Controls Mechanically Regulated Splicing Of the Adapte...mentioning

confidence: 99%

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Mechanical control of the splicing factor PTBP1 regulates extracellular matrix stiffness-induced cell proliferation and mechanomemory

Tseng,

Sun,

Salem

et al. 2024

Preprint

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Cells sense and respond to mechanical cues from their environment. Mechanical cues are important for many biological processes, including embryonic development, ageing, cellular homeostasis, and diseases. Cells translate mechanical cues into cellular biochemical signals that govern cellular behaviour, like cell proliferation or migration, via a process called mechanotransduction. However, this process and the proteins involved remain incompletely understood. Here, we present an unbiased and large-scale approach to identify proteins involved in mechanotransduction. The screen revealed that the splicing factor PTBP1 is a novel mechanotransducer. We show that the nuclear localisation of PTBP1 depends on extracellular matrix stiffness, cell density, and the actomyosin-based contractility of the cell. Furthermore, we demonstrate that PTBP1 promotes the mechanosensitive splicing of the adapter protein Numb and that alternative splicing of Numb is crucial for matrix stiffness-induced cell proliferation and mechanomemory. Our results support the idea that changes in alternative splicing are an integral part of mechanotransduction and provide a mechanism by which matrix stiffness regulates cell proliferation and the formation of a mechanomemory in cells.

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Section: Discussionmentioning

confidence: 99%

Section: Ptbp1 Controls Mechanically Regulated Splicing Of the Adapte...mentioning

confidence: 99%

Mechanical control of the splicing factor PTBP1 regulates extracellular matrix stiffness-induced cell proliferation and mechanomemory

Tseng,

Sun,

Salem

et al. 2024

Preprint

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PTBP1 knockdown impairs autophagy flux and inhibits gastric cancer progression through TXNIP-mediated oxidative stress

Wang,

Qin

et al. 2024

Cell Mol Biol Lett

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Background Gastric cancer (GC) is a prevalent malignant tumor, and the RNA-binding protein polypyrimidine tract-binding protein 1 (PTBP1) has been identified as a crucial factor in various tumor types. Moreover, abnormal autophagy levels have been shown to significantly impact tumorigenesis and progression. Despite this, the precise regulatory mechanism of PTBP1 in autophagy regulation in GC remains poorly understood. Methods To assess the expression of PTBP1 in GC, we employed a comprehensive approach utilizing western blot, real-time quantitative polymerase chain reaction (RT–qPCR), and bioinformatics analysis. To further identify the downstream target genes that bind to PTBP1 in GC cells, we utilized RNA immunoprecipitation coupled with sequencing (si-PTBP1 RNA-seq). To evaluate the impact of PTBP1 on gastric carcinogenesis, we conducted CCK-8 assays, colony formation assays, and GC xenograft mouse model assays. Additionally, we utilized a transmission electron microscope, immunofluorescence, flow cytometry, western blot, RT–qPCR, and GC xenograft mouse model experiments to elucidate the specific mechanism underlying PTBP1’s regulation of autophagy in GC. Results Our findings indicated that PTBP1 was significantly overexpressed in GC tissues compared with adjacent normal tissues. Silencing PTBP1 resulted in abnormal accumulation of autophagosomes, thereby inhibiting GC cell viability both in vitro and in vivo. Mechanistically, interference with PTBP1 promoted the stability of thioredoxin-interacting protein (TXNIP) mRNA, leading to increased TXNIP-mediated oxidative stress. Consequently, this impaired lysosomal function, ultimately resulting in blockage of autophagic flux. Furthermore, our results suggested that interference with PTBP1 enhanced the antitumor effects of chloroquine, both in vitro and in vivo. Conclusion PTBP1 knockdown impairs GC progression by directly binding to TXNIP mRNA and promoting its expression. Based on these results, PTBP1 emerges as a promising therapeutic target for GC. Graphical Abstract

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PTBP1 promotes hepatocellular carcinoma progression by regulating the skipping of exon 9 in NUMB pre-mRNA

Cited by 2 publications

References 32 publications

Mechanical control of the splicing factor PTBP1 regulates extracellular matrix stiffness-induced cell proliferation and mechanomemory

Mechanical control of the splicing factor PTBP1 regulates extracellular matrix stiffness-induced cell proliferation and mechanomemory

PTBP1 knockdown impairs autophagy flux and inhibits gastric cancer progression through TXNIP-mediated oxidative stress

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