Heat Shock Protein 90α–Dependent B‐Cell‐2–Associated Transcription Factor 1 Promotes Hepatocellular Carcinoma Proliferation by Regulating MYC Proto‐Oncogene c‐MYC mRNA Stability

Zhou, Xueqiong; Wen, Ying; Tian, Ye; He, Miao; Ke, Xiangyu; Huang, Zhizhou; He, Yangfan; Liu, Lixia; Scharf, Annette; Lu, Meiting; Zhang, Guowei; Deng, Yaotang; Yan, Yi; Mayer, Matthias P.; Chen, Xuemei; Zou, Fei

doi:10.1002/hep.30172

Cited by 39 publications

(48 citation statements)

References 44 publications

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“…However, the number of living cells detected by CCK-8 can be influenced by various factors such as cell proliferation, pyroptosis, necrosis, apoptosis, autophagy and so on [33]. HSP90α, the precursor protein of HIBDAP, plays an important role in promoting cell proliferation [34,35]. Therefore, groups of 10 µM and 20 µM had higher cell viability may because of the balance of pyroptosis and proliferation.…”

Section: Discussionmentioning

confidence: 99%

Peptidome Analysis of Cerebrospinal Fluid in Neonates with Hypoxic-Ischemic Brain Damage

Hou

Yuan

Wang

et al. 2020

Preprint

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Hypoxic-ischemic brain injury (HIBD) causes neonatal death and serious neurological disability; however, there are currently no promising therapies for it excepting cooling. Therefore, in this study, we used peptidome analysis to identify differentially expressed peptides in cerebrospinal fluid (CSF) of neonates with HIBD or controls, which may give a foundation for finding new promising drugs of neonatal HIBD. CSF samples were collected from neonates with HIBD (n = 4) or controls (n = 4). ITRAQ LC-MS/MS was used to identify differentially expressed peptides between two groups. Effects of the peptide from heat shock protein 90-alpha (HSP90α/HSP90AA1) on cell viability and pyroptosis under oxygen and glucose deprivation (OGD) were analyzed using cell counting kit-8 (CCK-8) assay and Annexin V-fluorescein isothiocyanate (FITC) Assay. Expressions of NLRP3, ASC and Caspase-1 were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. Compared with the control group, one peptide significantly up-regulated and thirty-four peptides significantly down-regulated in the CSF of neonates with HIBD. A fragment of HSP90α/HSP90AA1 is the 2671.5 Da peptide (HSQFIGYPITLFVEKER), one of the down-regulated peptides in neonatal HIBD. This peptide, we named it HIBDAP, inhibited pyroptosis of PC12 cells under OGD by suppressing expressions of NLRP3, ASC and Caspase-1. The results of our study identified the characterization and expression profiles of peptides in CSF of neonatal HIBD. Several meaningful peptides such as HIBDAP may play significant roles in neonatal HIBD and may provide new therapeutic targets for neonatal HIBD.

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Section: Discussionmentioning

confidence: 99%

Peptidome Analysis of Cerebrospinal Fluid in Neonates with Hypoxic-Ischemic Brain Damage

Hou

Yuan

Wang

et al. 2020

Preprint

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“…The known upregulated P16 INK4A (an oncosuppressor gene) is linked to the HSP90 mild overexpression (Pascale et al, 2005). Besides, B‐cell lymphoma 2 (Bcl‐2)‐associated transcription factor 1 (Bclaf1) is frequently upregulated in HCC, and its upregulation is associated with poor prognosis and decreased survival (X. Zhou et al, 2019). To exert its effect, Bclaf1 must interact with the HSP90α and it was reported that in HCC tissue samples, Hsp90α–Bclaf1 interaction was enhanced (X. Zhou et al, 2019).…”

Section: Hsp90 Expression In Hccmentioning

confidence: 99%

“…Besides, B‐cell lymphoma 2 (Bcl‐2)‐associated transcription factor 1 (Bclaf1) is frequently upregulated in HCC, and its upregulation is associated with poor prognosis and decreased survival (X. Zhou et al, 2019). To exert its effect, Bclaf1 must interact with the HSP90α and it was reported that in HCC tissue samples, Hsp90α–Bclaf1 interaction was enhanced (X. Zhou et al, 2019). As another evidence about HSP90 expression in HCC, it was shown that following radiofrequency ablation, the cellular expression of HSP90 in HCC tissue increased (G. Schueller et al, 2004).…”

Section: Hsp90 Expression In Hccmentioning

confidence: 99%

“…HSP90 expression upregulates in HCC and it has two cytosolic isoforms: (a) Major form is Hsp90α (stress‐inducible), which has two members of HSP90α 1 and HSP90α 2 , (b) Minor form is HSP90β (constitutive; Powers & Workman, 2007). HSP90α is an essential factor for modulating MYC proto‐oncogene (c‐Myc) mRNA stability by Bclaf1, and interaction of HSP90α‐Bclaf1 elevates HCC in the tissue (X. Zhou et al, 2019). In HepG2 cell line, hepatitis B virus X (HBx) protein upregulates c‐Myc expression by using Ras/Raf/ERK1/2 signaling cascades, thus leading to an increased HSP90α expression (Li et al, 2010).…”

Section: Mechanism Of Actionmentioning

confidence: 99%

“…Gp96 has been reported as a possible and accurate predictive biomarker for cancer recurrence in HCC cases following curative resection (Ji et al, 2019). Bclaf1 expression can indicate an appropriate biomarker in HCC and possibly in other cancer cases (X. Zhou et al, 2019). Alternative splicing of the Numb ( Numb has been detected in Drosophila as an important factor for cell fate) can be an effective predictive biomarker in HCC and is also tractable (Lu et al, 2015).…”

Section: Hsp90 As a Biomarker In Hccmentioning

confidence: 99%

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The role of HSP90 molecular chaperones in hepatocellular carcinoma

Nouri‐Vaskeh

Alizadeh

Hajiasgharzadeh

et al. 2020

Journal Cellular Physiology

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Misfolded proteins have enhanced formation of toxic oligomers and nonfunctional protein copies lead to recruiting wild‐type protein types. Heat shock protein 90 (HSP90) is a molecular chaperone generated by cells that are involved in many cellular functions through regulation of folding and/or localization of large multi‐protein complexes as well as client proteins. HSP90 can regulate a number of different cellular processes including cell proliferation, motility, angiogenesis, signal transduction, and adaptation to stress. HSP90 makes the mutated oncoproteins able to avoid misfolding and degradation and permits the malignant transformation. As a result, HSP90 is an important factor in several signaling pathways associated with tumorigenicity, therapy resistance, and inhibiting apoptosis. Clinically, the upregulation of HSP90 expression in hepatocellular carcinoma (HCC) is linked with advanced stages and inappropriate survival in cases suffering from this kind of cancer. The present review comprehensively assesses HSP90 functions and its possible usefulness as a potential diagnostic biomarker and therapeutic option for HCC.

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BCLAF1 binds SPOP to stabilize PD-L1 and promotes the development and immune escape of hepatocellular carcinoma

Yu,

Wu,

Zhu

et al. 2024

Cell. Mol. Life Sci.

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Interaction between programmed death-1 (PD-1) ligand 1 (PD-L1) on tumor cells and PD-1 on T cells allows tumor cells to evade T cell-mediated immune surveillance. Strategies targeting PD-1/PD-L1 have shown clinical benefits in a variety of cancers. However, limited response rates in hepatocellular carcinoma (HCC) have prompted us to investigate the molecular regulation of PD-L1. Here, we identify B cell lymphoma-2-associated transcription factor 1 (BCLAF1) as a key PD-L1 regulator in HCC. Specifically, BCLAF1 interacts with SPOP, an E3 ligase that mediates the ubiquitination and degradation of PD-L1, thereby competitively inhibiting SPOP-PD-L1 interaction and subsequent ubiquitination and degradation of PD-L1. Furthermore, we determined an SPOP-binding consensus (SBC) motif mediating the BCLAF1-SPOP interaction on BCLAF1 protein and mutation of BCLAF1-SBC motif disrupts the regulation of the SPOP-PD-L1 axis. In addition, BCLAF1 expression was positively correlated with PD-L1 expression and negatively correlated with biomarkers of T cell activation, including CD3 and CD8, as well as with the level of immune cell infiltration in HCC tissues. Besides, BCLAF1 depletion leads to a significant reduction of PD-L1 expression in vitro, and this reduction of PD-L1 promoted T cell-mediated cytotoxicity. Notably, overexpression of BCLAF1 sensitized tumor cells to checkpoint therapy in an in vitro HCC cells-Jurkat cells co-culture model, whereas BCLAF1-SBC mutant decreased tumor cell sensitivity to checkpoint therapy, suggesting that BCLAF1 and its SBC motif serve as a novel therapeutic target for enhancing anti-tumor immunity in HCC.

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Heat Shock Protein 90α–Dependent B‐Cell‐2–Associated Transcription Factor 1 Promotes Hepatocellular Carcinoma Proliferation by Regulating MYC Proto‐Oncogene c‐MYC mRNA Stability

Abstract: Our findings suggest that Bclaf1 affects HCC progression by manipulating c-MYC mRNA stability and that the Hsp90α/Bclaf1/c-Myc axis might be a potential target for therapeutic intervention in HCC.

Cited by 39 publications

References 44 publications

Peptidome Analysis of Cerebrospinal Fluid in Neonates with Hypoxic-Ischemic Brain Damage

Peptidome Analysis of Cerebrospinal Fluid in Neonates with Hypoxic-Ischemic Brain Damage

The role of HSP90 molecular chaperones in hepatocellular carcinoma

BCLAF1 binds SPOP to stabilize PD-L1 and promotes the development and immune escape of hepatocellular carcinoma

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