Impact of HDAC Inhibitors on Protein Quality Control Systems: Consequences for Precision Medicine in Malignant Disease

Kulka, Linda Anna Michelle; Fangmann, Pia-Victoria; Panfilova, Diana; Olzscha, Heidi

doi:10.3389/fcell.2020.00425

Cited by 34 publications

(26 citation statements)

References 274 publications

(269 reference statements)

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“…We found that trichostatin A and vorinostat, which are pan-HDAC inhibitors of class I and II HDACs, had a potential therapeutic effect on the patients with lower immune or stromal scores and worse survival. HDACs play a critical role in the regulation of transcription by promoting the deacetylation of histone proteins ( Kulka et al, 2020 ). The upregulation of specific HDACs have been found in different cancers, including SARC ( Tang et al, 2017 ; Banik et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of Tumor Microenvironment-Related Prognostic Genes in Sarcoma

et al. 2021

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AimImmune cells that infiltrate the tumor microenvironment (TME) are associated with cancer prognosis. The aim of the current study was to identify TME related gene signatures related to the prognosis of sarcoma (SARC) by using the data from The Cancer Genome Atlas (TCGA).MethodsImmune and stromal scores were calculated by estimation of stromal and immune cells in malignant tumor tissues using expression data algorithms. The least absolute shrinkage and selection operator (lasso) based cox model was then used to select hub survival genes. A risk score model and nomogram were used to predict the overall survival of patients with SARC.ResultsWe selected 255 patients with SARC for our analysis. The Kaplan–Meier method found that higher immune (p = 0.0018) or stromal scores (p = 0.0022) were associated with better prognosis of SARC. The estimated levels of CD4+ (p = 0.0012) and CD8+ T cells (p = 0.017) via the tumor immune estimation resource were higher in patients with SARC with better overall survival. We identified 393 upregulated genes and 108 downregulated genes (p < 0.05, fold change >4) intersecting between the immune and stromal scores based on differentially expressed gene (DEG) analysis. The univariate Cox analysis of each intersecting DEG and subsequent lasso-based Cox model identified 11 hub survival genes (MYOC, NNAT, MEDAG, TNFSF14, MYH11, NRXN1, P2RY13, CXCR3, IGLV3-25, IGHV1-46, and IGLV2-8). Then, a hub survival gene-based risk score gene signature was constructed; higher risk scores predicted worse SARC prognosis (p < 0.0001). A nomogram including the risk scores, immune/stromal scores and clinical factors showed a good prediction value for SARC overall survival (C-index = 0.716). Finally, connectivity mapping analysis identified that the histone deacetylase inhibitors trichostatin A and vorinostat might have the potential to reverse the harmful TME for patients with SARC.ConclusionThe current study provided new indications for the association between the TME and SARC. Lists of TME related survival genes and potential therapeutic drugs were identified for SARC.

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Section: Discussionmentioning

confidence: 99%

Identification of Tumor Microenvironment-Related Prognostic Genes in Sarcoma

et al. 2021

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“…For example, a non-histone target of HDACs is p53, which is a tumor suppressor protein. Acetylated p53 induces apoptosis and autophagy in chronic myeloid leukemia cells [ 21 , 22 ]. The other non-histone targets of acetylation include tubulin, heat-shock proteins, NF-κB subunit p65, E2Fs, and myoblast determination proteins.…”

Section: Discussionmentioning

confidence: 99%

Differential Effects of Histone Deacetylases on the Expression of NKG2D Ligands and NK Cell-Mediated Anticancer Immunity in Lung Cancer Cells

et al. 2021

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Histone acetylation is an epigenetic mechanism that regulates the expression of various genes, such as natural killer group 2, member D (NKG2D) ligands. These NKG2D ligands are the key molecules that activate immune cells expressing the NKG2D receptor. It has been observed that cancer cells overexpress histone deacetylases (HDACs) and show reduced acetylation of nuclear histones. Furthermore, HDAC inhibitors are known to upregulate the expression of NKG2D ligands. Humans have 18 known HDAC enzymes that are divided into four classes. At present, it is not clear which types of HDAC are involved in the expression of NKG2D ligands. We hypothesized that specific types of HDAC genes might be responsible for altering the expression of NKG2D ligands. In this study, we monitored the expression of NKG2D ligands and major histocompatibility complex (MHC) class I molecules in lung cancer cells which were treated with six selective HDAC inhibitors and specific small interfering RNAs (siRNAs). We observed that treatment with FK228, which is a selective HDAC1/2 inhibitor, also known as Romidepsin, induced NKG2D ligand expression at the transcriptional and proteomic levels in two different lung cancer cell lines. It also caused an increase in the susceptibility of NCI-H23 cells to NK cells. Silencing HDAC1 or HDAC2 using specific siRNAs increased NKG2D ligand expression. In conclusion, it appears that HDAC1 and HDAC2 might be the key molecules regulating the expression of NKG2D ligands. These results imply that specifically inhibiting HDAC1 and HDAC2 could induce the expression of NKG2D ligands and improve the NK cell-mediated anti-cancer immunity.

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“…Previous studies indicated that KDACs, especially KDAC6, play an essential role in protein quality control mechanisms [ 57 ]. Thus, the inhibition of KDAC to maintain proteostasis has been proposed to have therapeutic potential in cancer [ 58 ]. Indeed, several studies have demonstrated the potential therapeutic value of combining proteostasis regulators such as KDACIs and proteasome inhibitors in cancer [ 59 , 60 ].…”

Section: Discussionmentioning

confidence: 99%

Quantitative Proteomic Approach Reveals Altered Metabolic Pathways in Response to the Inhibition of Lysine Deacetylases in A549 Cells under Normoxia and Hypoxia

Martín-Bernabé

Tarragó-Celada

Cunin

et al. 2021

IJMS

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Growing evidence is showing that acetylation plays an essential role in cancer, but studies on the impact of KDAC inhibition (KDACi) on the metabolic profile are still in their infancy. Here, we analyzed, by using an iTRAQ-based quantitative proteomics approach, the changes in the proteome of KRAS-mutated non-small cell lung cancer (NSCLC) A549 cells in response to trichostatin-A (TSA) and nicotinamide (NAM) under normoxia and hypoxia. Part of this response was further validated by molecular and biochemical analyses and correlated with the proliferation rates, apoptotic cell death, and activation of ROS scavenging mechanisms in opposition to the ROS production. Despite the differences among the KDAC inhibitors, up-regulation of glycolysis, TCA cycle, oxidative phosphorylation and fatty acid synthesis emerged as a common metabolic response underlying KDACi. We also observed that some of the KDACi effects at metabolic levels are enhanced under hypoxia. Furthermore, we used a drug repositioning machine learning approach to list candidate metabolic therapeutic agents for KRAS mutated NSCLC. Together, these results allow us to better understand the metabolic regulations underlying KDACi in NSCLC, taking into account the microenvironment of tumors related to hypoxia, and bring new insights for the future rational design of new therapies.

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Impact of HDAC Inhibitors on Protein Quality Control Systems: Consequences for Precision Medicine in Malignant Disease

Cited by 34 publications

References 274 publications

Identification of Tumor Microenvironment-Related Prognostic Genes in Sarcoma

Identification of Tumor Microenvironment-Related Prognostic Genes in Sarcoma

Differential Effects of Histone Deacetylases on the Expression of NKG2D Ligands and NK Cell-Mediated Anticancer Immunity in Lung Cancer Cells

Quantitative Proteomic Approach Reveals Altered Metabolic Pathways in Response to the Inhibition of Lysine Deacetylases in A549 Cells under Normoxia and Hypoxia

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