Voltage‐gated sodium channels β3 subunit promotes tumorigenesis in hepatocellular carcinoma by facilitating p53 degradation

Li, Shuai; Han, Jiadi; Guo, Guili; Sun, Yudi; Zhang, Tingting; Zhao, Ming; Xu, Yijia; Cui, Yong; Liu, Yanfeng; Zhang, Jinghai

doi:10.1002/1873-3468.13641

Cited by 11 publications

(5 citation statements)

References 48 publications

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“…The role of SCN3B in p53-dependent cellular physiology is obscure. According to one report, it promotes p53-dependent apoptosis [126], and according to another report, it may be an element of the negative-feedback loop in the p53 signaling pathway [127]. Even though the expression of another gene, GABRD, regulating the transport of molecules across plasma membrane was not reported to be p53-dependent in any individual report, the gene was found to be activated by p53 in 12 high-throughput studies, and the enhancer of the gene is bound by p53 [18].…”

Section: Atypical Targets Of P53mentioning

confidence: 99%

The p53 protein – not only the guardian of the genome

Rusin

2024

Postepy Biochem

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The p53 tumor suppressor protein is best known as an activator of cell cycle arrest and apoptosis. Only a fraction of p53-activated genes encode proteins affecting cellular replication and various forms of cell death (apoptosis, ferroptosis, autophagy). The p53-regulated genes can be divided into so-called the core transcriptional program, which comprises genes activated in most cell types by most activators, and into the group of genes activated in in cell- or stress-specific manner. Activation of p53 occurs via the extensive set of posttranslational modifications, which adjust its stability, interaction with other transcription regulators, and its ability to form a tetramer. Surprisingly, in mouse models, the activation of the best-studied p53 target genes encoding the inhibitor of the cell cycle (CDKN1A) or the inducers of apoptosis (e.g. NOXA, PUMA) is dispensable for protection against cancers. Thus, the non-classical functions of p53 must be studied to better understand its tumor suppressive mechanisms.

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Section: Atypical Targets Of P53mentioning

confidence: 99%

The p53 protein – not only the guardian of the genome

Rusin

2024

Postepy Biochem

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“…Surprisingly, a recent work on hepatocellular carcinoma (HCC) found contrasting results with the pro-apoptotic function of VGSCs β3-subunit. By using HepG2, a HCC cell line, Li and cols (Li et al, 2020) demonstrated that β3 subunit knockdown induces cell cycle arrest in HepG2 cells and attenuates tumor growth in nude mice. In addition, their findings indicate that β3 could bind to p53, which promotes its ubiquitination and degradation, leading to a lower level of p53.…”

Section: Resisting Apoptosismentioning

confidence: 99%

“…These contrasting results could be due to the molecular regulation of p53 ubiquitination and degradation carried by MDM2, a negative regulator of this tumor suppressor (Koo et al, 2022). The binding of β3 to p53 could stabilize the p53/ MDM2 complex promoting p53 ubiquitination and degradation (Li et al, 2020), whereas the exogenous overexpression of β3 could competitively promote the release of p53 from such complex and apoptosis in Saos-2 and T98G cells (Adachi et al, 2004). An additional study showed that β3 expression was totally absent in two metastatic BCa cell lines, whereas the other three VGSCs βsubunits were present at different levels of expression (Chioni et al, 2009).…”

Section: Resisting Apoptosismentioning

confidence: 99%

Voltage-gated sodium channels: from roles and mechanisms in the metastatic cell behavior to clinical potential as therapeutic targets

2023

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During the second half of the last century, the prevalent knowledge recognized the voltage-gated sodium channels (VGSCs) as the proteins responsible for the generation and propagation of action potentials in excitable cells. However, over the last 25 years, new non-canonical roles of VGSCs in cancer hallmarks have been uncovered. Their dysregulated expression and activity have been associated with aggressive features and cancer progression towards metastatic stages, suggesting the potential use of VGSCs as cancer markers and prognostic factors. Recent work has elicited essential information about the signalling pathways modulated by these channels: coupling membrane activity to transcriptional regulation pathways, intracellular and extracellular pH regulation, invadopodia maturation, and proteolytic activity. In a promising scenario, the inhibition of VGSCs with FDA-approved drugs as well as with new synthetic compounds, reduces cancer cell invasion in vitro and cancer progression in vivo. The purpose of this review is to present an update regarding recent advances and ongoing efforts to have a better understanding of molecular and cellular mechanisms on the involvement of both pore-forming α and auxiliary β subunits of VGSCs in the metastatic processes, with the aim at proposing VGSCs as new oncological markers and targets for anticancer treatments.

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“…The sodium voltage-gated channel beta subunit 3 (SCN3B) controls electrolytes and contributes to the pacemaking in the heart and has an effect on intracellular trafficking (Ishikawa et al, 2012). It also suppresses senescence and apoptosis via its interaction with p53 and thus, is considered to be an oncogenic factor (Li et al, 2020).…”

Section: Scn3b (-)mentioning

confidence: 99%

Gene co-expression analyses of health(span) across multiple species

Möller

Saul²,

Barrantes

et al. 2021

Preprint

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Health(span)-related gene clusters/modules were recently identified based on knowledge about the cross-species genetic basis of health, to interpret transcriptomic datasets describing health-related interventions. However, the cross-species comparison of health-related observations reveals a lot of heterogeneity, not least due to widely varying health(span) definitions and study designs, posing a challenge for the exploration of conserved healthspan modules and, specifically, their transfer across species. To improve the identification and exploration of conserved/transferable healthspan modules, here we apply an established workflow based on gene co-expression network analyses employing GEO/ArrayExpress data for human and animal models, and perform a comprehensive meta-analysis of the resulting modules related to health(span), yielding a small set of health(span) candidate genes, backed by the literature. For each experiment, WGCNA (weighted gene correlation network analysis) was thus used to infer modules of genes which correlate in their expression with a "health phenotype score" and to determine the most-connected (hub) genes for each such module, and their interactions. After mapping these hub genes to their human orthologs, 12 health(span) genes were identified in at least two species (ACTN3, ANK1, MRPL18, MYL1, PAXIP1, PPP1CA, SCN3B, SDCBP, SKIV2L, TUBG1, TYROBP, WIPF1), for which enrichment analysis by g:profiler finds an association with actin filament-based movement and associated organelles as well as muscular structures. We conclude that a meta-study of hub genes from co-expression network analyses for the complex phenotype health(span), across multiple species, can yield molecular-mechanistic insights and can direct experimentalists to further investigate the contribution of individual genes and their interactions to health(span).

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Voltage‐gated sodium channels β3 subunit promotes tumorigenesis in hepatocellular carcinoma by facilitating p53 degradation

Cited by 11 publications

References 48 publications

The p53 protein – not only the guardian of the genome

The p53 protein – not only the guardian of the genome

Voltage-gated sodium channels: from roles and mechanisms in the metastatic cell behavior to clinical potential as therapeutic targets

Gene co-expression analyses of health(span) across multiple species

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