Significance of prohibitin domain family in tumorigenesis and its implication in cancer diagnosis and treatment

Yang, Jie; B, Li; He, Qing-Yu

doi:10.1038/s41419-018-0661-3

Cited by 68 publications

(91 citation statements)

References 134 publications

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“…Prohibitin (PHB, also known as PHB1) is a highly conserved and ubiquitously expressed protein localized to different cellular compartments, including the lipid raft of the plasma membrane, mitochondria, cytoplasm or nucleus, and has diverse biological functions [23,24]. In A549 lung cancer cells, an increase in surface PHB expression has been shown to prevent the apoptosis of cancer cells and render them more resistant to paclitaxel [25].…”

Section: Introductionmentioning

confidence: 99%

A novel c-Kit/phospho-prohibitin axis enhances ovarian cancer stemness and chemoresistance via Notch3—PBX1 and β-catenin—ABCG2 signaling

et al. 2020

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Background: The underlying mechanism involved in ovarian cancer stemness and chemoresistance remains largely unknown. Here, we explored whether the regulation of c-Kit and plasma membrane prohibitin (PHB) affects ovarian cancer stemness and chemotherapy resistance.Methods: Mass spectrum analysis and an in vitro kinase assay were conducted to examine the phosphorylation of PHB at tyrosine 259 by c-Kit. The in vitro effects of c-Kit on membrane raft-PHB in ovarian cancer were determined using tissue microarray (TMA)-based immunofluorescence, western blotting, immunoprecipitation, colony and spheroid formation, cell migration and cell viability assays. In vivo tumor initiation and carboplatin treatment were conducted in nude mice.Results: We found that c-Kit and PHB colocalized in the raft domain and were positively correlated in human ovarian serous carcinoma. c-Kit interacted with PHB and facilitated the phosphorylation of PHB at tyrosine 259 (phospho-PHB Y259 ) in the membrane raft to enhance ovarian cancer cell motility. The generation of SKOV3GL-G4, a metastatic phenotype of SKOV3 green fluorescent protein and luciferase (GL) ovarian cancer cells, in xenograft murine ascites showed a correlation between metastatic potential and stem cell characteristics, as indicated by the expression of c-Kit, Notch3, Oct4, Nanog and SOX2. Further study revealed that after activation by c-Kit, raft-phospho-PHB Y259 interacted with Notch3 to stabilize Notch3 and increase the downstream target PBX1. Downregulation of raft-phospho-PHB Y259 increased the protein degradation of Notch3 through a lysosomal pathway and inhibited the β-catenin-ABCG2 signaling pathway. Moreover, raft-phospho-PHB Y259 played an important role in ovarian cancer stemness and tumorigenicity as well as resistance to platinum drug treatment in vitro and in vivo.Conclusions: These findings thus reveal a hitherto unreported interrelationship between c-Kit and PHB as well as the effects of raft-phospho-PHB Y259 on ovarian cancer stemness and tumorigenicity mediated by the Notch3 and β-catenin signaling pathways. Targeting the c-Kit/raft-phospho-PHB Y259 axis may provide a new therapeutic strategy for treating patients with ovarian cancer.

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Section: Introductionmentioning

confidence: 99%

A novel c-Kit/phospho-prohibitin axis enhances ovarian cancer stemness and chemoresistance via Notch3—PBX1 and β-catenin—ABCG2 signaling

et al. 2020

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“…Although PHB has been studied extensively, the subsets of PHB from different subcellular fractions deserve further exploration as their distinct functions and pathological significances remain elusive [27]. In this study, we reported for the first time that the higher expression level of nuclear PHB is significantly associated with breast cancer metastasis.…”

Section: Discussionmentioning

confidence: 83%

Prohibitin participates in the HIRA complex to promote cell metastasis in breast cancer cell lines

Huang

Liu

2020

FEBS Open Bio

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Prohibitin (PHB) is a highly conserved, ubiquitously expressed, multifunctional protein with a well‐characterized function as a chaperone‐stabilizing mitochondrial proteins. Recently it was reported that nuclear PHB participates in HIRA chaperone complexes and regulates downstream gene expression via cell cycle independent deposition of H3.3 into DNA. However, the role of PHB in cancer progression remains controversial with conflicting reports in the literature, perhaps due to its cell type‐dependent subcellular localization. Here, we report that the increased expression of nuclear PHB is positively correlated with metastasis of breast cancer cell lines. We showed PHB participates in the HIRA complex by interacting with HIRA through the linker region of the PHB domain and stabilizes all components of the HIRA complex in breast cancer. Overexpression of nuclear PHB resulted in a higher enrichment of histone H3.3 deposited by the HIRA complex at the promoters of mesenchymal markers. This coincided with an increased gene expression level of these markers, and induced EMT in breast cancer. Overall, these molecular and structural mechanisms suggest that nuclear PHB could hold promise as a potential target for cancer therapy.

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“…Loss of p53 and ARF are classical features of glioblastoma (Kim et al, 2012; Mao et al, 2012; Zheng et al, 2008). PHB is required for correct localization of Raf-1 in response to Ras activation and couples EGFR signaling to Ras-Raf-MEK-ERK activation, as well as for mitochondrial functions (Rajalingam and Rudel, 2005; Wei et al, 2017; Yang et al, 2018b). Activation of oxidative and ER stress programs are captured by aberrant activation of proteins such as PRDX4 (Bulleid and Ellgaard, 2011; Zito, 2013).…”

Section: Resultsmentioning

confidence: 99%

Single-cell based elucidation of molecularly-distinct glioblastoma states and drug sensitivity

Ding

Burgenske

Zhao

et al. 2019

Preprint

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Glioblastoma heterogeneity and plasticity remain controversial, with proposed subtypes representing the average of highly heterogeneous admixtures of independent transcriptional states. Single-cell, protein-activity-based analysis allowed full quantification of >6,000 regulatory and signaling proteins, thus providing a previously unattainable single-cell characterization level. This helped identify four novel, molecularly distinct subtypes that successfully harmonize across multiple GBM datasets, including previously published bulk and single-cell profiles and single cell profiles from seven orthotopic PDX models, representative of prior subtype diversity. GBM is thus characterized by the plastic coexistence of single cells in two mutually-exclusive developmental lineages, with additional stratification provided by their proliferative potential. Consistently, all previous subtypes could be recapitulated by single-cell mixtures drawn from newly identified states. Critically, drug sensitivity was predicted and validated as highly state-dependent, both in single-cell assays from patient-derived explants and in PDX models, suggesting that successful treatment requires combinations of multiple drugs targeting these distinct tumor states. Significance We propose a new, 4-subtype GBM classification, which harmonizes across bulk and single-cell datasets. Single-cell mixtures from these subtypes effectively recapitulate all prior classifications, suggesting that the latter are a byproduct of GBM heterogeneity. Finally, we predict single-cell level activity of three clinically-relevant drugs, and validate them in patient-derived explant.

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Significance of prohibitin domain family in tumorigenesis and its implication in cancer diagnosis and treatment

Cited by 68 publications

References 134 publications

A novel c-Kit/phospho-prohibitin axis enhances ovarian cancer stemness and chemoresistance via Notch3—PBX1 and β-catenin—ABCG2 signaling

A novel c-Kit/phospho-prohibitin axis enhances ovarian cancer stemness and chemoresistance via Notch3—PBX1 and β-catenin—ABCG2 signaling

Prohibitin participates in the HIRA complex to promote cell metastasis in breast cancer cell lines

Single-cell based elucidation of molecularly-distinct glioblastoma states and drug sensitivity

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