C-Terminal HSP90 Inhibitors Block the HIF-1 Hypoxic Response by Degrading HIF-1α through the Oxygen-Dependent Degradation Pathway

Kataria, Nalin; Martinez, Chloe-Anne; Kerr, Bernadette; Zaiter, Samantha S.; Morgan, Monica; McAlpine, Shelli R.; Cook, Kristina M.

doi:10.33594/000000152

Cited by 28 publications

(16 citation statements)

References 36 publications

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“…It has been widely reported that low oxygenation, which arises as a consequence of imbalance between the oxygen supply and oxygen consumption, is a hallmark of solid tumors [ 43 ]. HIF-1α is a crucial regulator of oxygen homeostasis, and its transcription is modulated by Hsp90 expression [ 44 ]. As a chaperone, Hsp90 is the most abundant protein in the cytosol, and HSP90 interacts with HIF-1α and inhibits HIF-1α ubiquitination, ultimately leading to HIF-1α stabilization, which is correlated with tumorigenesis and progression [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Reduced HIF-1α Stability Induced by 6-Gingerol Inhibits Lung Cancer Growth through the Induction of Cell Death

Kim

Ku²,

Choi

et al. 2022

Molecules

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Lung cancer (LC) is the leading global cause of cancer-related death, and metastasis is a great challenge in LC therapy. Additionally, solid cancer, including lung, prostate, and colon cancer, are characterized by hypoxia. A low-oxygen state is facilitated by the oncogene pathway, which correlates with a poor cancer prognosis. Thus, we need to understand the related mechanisms in solid tumors to improve and develop new anticancer strategies. The experiments herein describe an anticancer mechanism in which heat shock protein 90 (HSP90) stabilizes HIF-1α, a master transcription factor of oxygen homeostasis that has been implicated in the survival, proliferation and malignant progression of cancers. We demonstrate the efficacy of 6-gingerol and the molecular mechanism by which 6-gingerol inhibits LC metastasis in different oxygen environments. Our results showed that cell proliferation was inhibited after 6-gingerol treatment. Additionally, HIF-1α, a transcriptional regulator, was found to be recruited to the hypoxia response element (HRE) of target genes to induce the transcription of a series of target genes, including MMP-9, vimentin and snail. Interestingly, we found that 6-gingerol treatment suppressed activation of the transcription factor HIF-1α by downregulating HSP90 under both normoxic and hypoxic conditions. Furthermore, an experiment in an in vivo xenograft model revealed decreased tumor growth after 6-gingerol treatment. Both in vitro and in vivo analyses showed the inhibition of metastasis through HIF-1α/HSP90 after 6-gingerol treatment. In summary, our study demonstrates that 6-gingerol suppresses proliferation and blocks the nuclear translocation of HIF-1α and activation of the EMT pathway. These data suggest that 6-gingerol is a candidate antimetastatic treatment for LC.

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Section: Discussionmentioning

confidence: 99%

Reduced HIF-1α Stability Induced by 6-Gingerol Inhibits Lung Cancer Growth through the Induction of Cell Death

Kim

Ku²,

Choi

et al. 2022

Molecules

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“…HDACi contributes to hyperacetylation of HSP90 with the repression of chaperone function, leading to the accumulation and vigorous degradation of immature HIF-1α mediated by pVHL [21]. In contrast, the research of Kataria et al [35] revealed that by targeting the ATPbinding pocket at the N-terminus of HSP90, HSP90 disassociates with HIF-1α, prompting the pVHL-independent degradation of HIF-1α. Therefore, we examine expression level of pVHL to determine whether pVHL directly mediates degradation of HIF-1α upon HDAC inhibition.…”

Section: Hdaci-induced Pvhl Independent Degradation Of Hif-1αmentioning

confidence: 98%

“…HSP90 promotes rapid accumulation of HIF-1α through the direct interaction with PAS domain of HIF-1α, thereby inducing structural change of HIF-1 heterodimer and stabilizing HIF-1α against pVHL-independent degradation [20,63]. Kataria et al [35] revealed that via inhibiting C-terminus of HSP90, proteasome degradation of HIF-1α would be initiated via PHD, even in hypoxia. Another subset of chaperone family member HSP70, is the cytosolic substrate of HDAC5 and HDACiinduced hyperacetylation renders HSP70 a higher affinity to HIF-1α, leading to the accelerated degradation and attenuated nuclear accumulation of HIF-1α [37].…”

Section: Plos Onementioning

confidence: 99%

Histone deacetylase inhibitor induced pVHL-independent degradation of HIF-1α and hierarchical quality control of pVHL via chaperone system

2021

PLoS ONE

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The mortality rate of ovarian cancer is increasing and the role of hypoxia inducible factor-1α (HIF-1α) in tumor progression has been confirmed. von Hippel-Lindau tumor suppressor protein (pVHL) binds HIF-1α and mediates proteasome degradation of HIF-1α. Besides, histone deacetylase inhibitor (HDACi) mitigates tumor growth via targeting HIF-1α, whereas underlying mechanism still requires investigation. In this research, we exposed ovarian cancer cell lines OV-90 and SKOV-3 to escalating concentrations of HDACi LBH589. As a result, cell viability was significantly suppressed and expression of HIF-1α was remarkably reduced along with decreased levels of signal molecules, including phosphoinositide 3-kinase (PI3K) and glycogen synthase kinase 3β (GSK3β) (P = 0.000). Interestingly, pVHL was expressed in a notably declining tendency (P = 0.000). Chaperone heat shock protein-70 (HSP70) was expressed in an ascending manner, whereas expression of chaperonin TCP-1α was reduced clearly (P = 0.000). Besides, co-inhibition of pVHL plus HDAC did not contribute to a remarkable difference in HIF-1α expression as compared with single HDAC inhibition. Furthermore, both cell lines were transfected with plasmids of VHL plus VHL binding protein-1 (VBP-1). Consequently, the expression of HIF-1α as well as lactate dehydrogenase-A (LDHA) was remarkably decreased (P = 0.000). These findings indicate HDACi may repress expression of HIF-1α via inhibiting PI3K and GSK3β and promote degradation of HIF-1α via HSP70, independent of pVHL. Additionally, a sophisticated network of HDAC and chaperones may involve in pVHL quality control.

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“…prolongs the half-life of the E2F1 protein by inhibiting its ubiquitination (MDM2 displaces SCFSKP2); influences cell proliferation [168] MYCBP2 Atypical E3 ubiquitin-protein ligase, which mediates ubiquitination of threonine and serine, instead of lysine residues AR, MYC [138] Tumorigenicity of AR-positive PCa cells [138] MYLIP E3 ubiquitin-protein ligase whose activity depends on E2 enzymes of the UBE2D family AR [172] AR activity [172] PIRH2 Ring finger protein with ubiquitin ligase activity Epsilon-COP [173]; HDAC1 [174] Regulation of the secretion of PSA [173]; AR signaling [174] pVHL Substrate recognition subunit of the VHL-Elongin B/C E3 ligase complex that targets the HIF-1/2 for proteasomal degradation under normoxia conditions AR (enhanced AR de-ubiquitination instead of inducing AR ubiquitination) [175]; HIF-1α [176] Suppression of AR activity [175]; HIF-1 hypoxic response [176] RNF2 Also known as RING1b or RING2; catalytic subunit of PRC1 TXNIP [177]; CCL2 [178] Cell cycle arrest and apoptosis [177]; metastasis in mice inoculated intracardially with PC-3M cells [178]…”

Section: Mdm2mentioning

confidence: 99%

Post-Translational Modifications That Drive Prostate Cancer Progression

Samaržija

2021

Biomolecules

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While a protein primary structure is determined by genetic code, its specific functional form is mostly achieved in a dynamic interplay that includes actions of many enzymes involved in post-translational modifications. This versatile repertoire is widely used by cells to direct their response to external stimuli, regulate transcription and protein localization and to keep proteostasis. Herein, post-translational modifications with evident potency to drive prostate cancer are explored. A comprehensive list of proteome-wide and single protein post-translational modifications and their involvement in phenotypic outcomes is presented. Specifically, the data on phosphorylation, glycosylation, ubiquitination, SUMOylation, acetylation, and lipidation in prostate cancer and the enzymes involved are collected. This type of knowledge is especially valuable in cases when cancer cells do not differ in the expression or mutational status of a protein, but its differential activity is regulated on the level of post-translational modifications. Since their driving roles in prostate cancer, post-translational modifications are widely studied in attempts to advance prostate cancer treatment. Current strategies that exploit the potential of post-translational modifications in prostate cancer therapy are presented.

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C-Terminal HSP90 Inhibitors Block the HIF-1 Hypoxic Response by Degrading HIF-1α through the Oxygen-Dependent Degradation Pathway

Abstract: This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission.

Cited by 28 publications

References 36 publications

Reduced HIF-1α Stability Induced by 6-Gingerol Inhibits Lung Cancer Growth through the Induction of Cell Death

Reduced HIF-1α Stability Induced by 6-Gingerol Inhibits Lung Cancer Growth through the Induction of Cell Death

Histone deacetylase inhibitor induced pVHL-independent degradation of HIF-1α and hierarchical quality control of pVHL via chaperone system

Post-Translational Modifications That Drive Prostate Cancer Progression

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