HDAC6 Plays a Noncanonical Role in the Regulation of Antitumor Immune Responses, Dissemination, and Invasiveness of Breast Cancer

Banik, Debarati; Noonepalle, Satish; Hadley, Melissa; Palmer, Erica; Gracia-Hernandez, Maria; Zevallos-Delgado, Christian; Manhas, Namratta; Simonyan, Hayk; Young, Colin N.; Popratiloff, Anastas; Chiappinelli, Katherine B.; Fernandes, Rohan; Sotomayor, Eduardo M.; Villagra, Alejandro

doi:10.1158/0008-5472.can-19-3738

Cited by 40 publications

(33 citation statements)

References 62 publications

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“…Of the class IIb HDACs, HDAC6 is a unique member that not only participates in histone acetylation and deacetylation, but also targets several non-histone substrates, such as α-tubulin, cortactin, and heat shock protein 90 (HSP90) to regulate cell proliferation, invasion and metastasis within the TME [ 55 ]. For example, HDAC6 plays a non-canonical role in the regulation of anti-tumor immune responses, as well as tumor invasion/dissemination in the setting of breast cancer [ 56 ]. HDAC10 is another important member regulating immune cell functions.…”

Section: Overview Of Epigenetic Pathways the Enzymes And Inhibitorsmentioning

confidence: 99%

Epigenetic modulation of antitumor immunity for improved cancer immunotherapy

et al. 2021

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Epigenetic mechanisms play vital roles not only in cancer initiation and progression, but also in the activation, differentiation and effector function(s) of immune cells. In this review, we summarize current literature related to epigenomic dynamics in immune cells impacting immune cell fate and functionality, and the immunogenicity of cancer cells. Some important immune-associated genes, such as granzyme B, IFN-γ, IL-2, IL-12, FoxP3 and STING, are regulated via epigenetic mechanisms in immune or/and cancer cells, as are immune checkpoint molecules (PD-1, CTLA-4, TIM-3, LAG-3, TIGIT) expressed by immune cells and tumor-associated stromal cells. Thus, therapeutic strategies implementing epigenetic modulating drugs are expected to significantly impact the tumor microenvironment (TME) by promoting transcriptional and metabolic reprogramming in local immune cell populations, resulting in inhibition of immunosuppressive cells (MDSCs and Treg) and the activation of anti-tumor T effector cells, professional antigen presenting cells (APC), as well as cancer cells which can serve as non-professional APC. In the latter instance, epigenetic modulating agents may coordinately promote tumor immunogenicity by inducing de novo expression of transcriptionally repressed tumor-associated antigens, increasing expression of neoantigens and MHC processing/presentation machinery, and activating tumor immunogenic cell death (ICD). ICD provides a rich source of immunogens for anti-tumor T cell cross-priming and sensitizing cancer cells to interventional immunotherapy. In this way, epigenetic modulators may be envisioned as effective components in combination immunotherapy approaches capable of mediating superior therapeutic efficacy.

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Section: Overview Of Epigenetic Pathways the Enzymes And Inhibitorsmentioning

confidence: 99%

Epigenetic modulation of antitumor immunity for improved cancer immunotherapy

et al. 2021

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“…Isotype-selective HDAC6 inhibitors decrease TGF-β-induced expression of type I collagen in lung fibroblasts ( Saito et al, 2017 ). Additionally, HDAC6 inhibition significantly decreases M2-like macrophages ( Knox et al, 2019 ; Banik et al, 2020 ), thus suggesting that HDAC6 inhibitors could be used to decrease M2-like macrophage-driven fibroblast activation. Besides, HDAC6 plays an essential role in viral entry ( Banerjee et al, 2014 ) and innate immunity ( Moreno-Gonzalo et al, 2018 ).…”

Section: Therapeutic Targeting Of Macrophage-induced Complications Inmentioning

confidence: 99%

Targeting Macrophages as a Therapeutic Option in Coronavirus Disease 2019

2020

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Immune cells of the monocyte/macrophage lineage are characterized by their diversity, plasticity, and variety of functions. Among them, macrophages play a central role in antiviral responses, tissue repair, and fibrosis. Macrophages can be reprogrammed by environmental cues, thus changing their phenotype during an antiviral immune response as the viral infection progresses. While M1-like macrophages are essential for the initial inflammatory responses, M2-like macrophages are critical for tissue repair after pathogen clearance. Numerous reports have evaluated the detrimental effects that coronaviruses, e.g., HCoV-229E, SARS-CoV, MERS-CoV, and SARS-CoV-2, have on the antiviral immune response and macrophage functions. In this review, we have addressed the breadth of macrophage phenotypes during the antiviral response and provided an overview of macrophage-coronavirus interactions. We also discussed therapeutic approaches to target macrophage-induced complications, currently under evaluation in clinical trials for coronavirus disease 2019 patients. Additionally, we have proposed alternative approaches that target macrophage recruitment, interferon signaling, cytokine storm, pulmonary fibrosis, and hypercoagulability.

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“…In line with these, we identi ed that the HDAC6 inhibitors can render cysteine-independent tumor cells sensitive to cysteine deprivation. HDAC6 is a unique member of the HDAC family that can regulate cell proliferation, metastasis, and invasion in tumors, and can also drive tumor progression and confer drug resistance in some cancers [62][63][64][65]. These observations suggest that HDAC6 is likely a reasonable molecular target in our system.…”

Section: Discussionmentioning

confidence: 81%

HDAC6 Inhibitors Sensitize Claudin-high Breast Cancer Cells to Cysteine Depletion via Activation of PKCγ Signaling

Alothaim

Charbonneau

Tang

2020

Preprint

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IntroductionTriple-negative breast cancer (TNBC) is a highly malignant breast cancer type with poor prognosis and lacks effective therapy. TNBC is not responsive to targeted therapy for hormone receptors and often exhibit resistance to current chemotherapeutic agents. Targeting tumor metabolism is an emergent strategy to treat cancer. Therefore, identification of tumor metabolic deregulations and development of effective targeted therapies are urgently needed.MethodsWe performed the epigenetic compound library screening in claudin-high breast tumor cells and identified therapeutical sensitizers to overcome the drug resistance of targeted cysteine-dependence therapy. Gene expression profiling were generated to analyze signaling pathways induced by the combined tubacin and cysteine deprivation treatment. Specific inhibitors, shRNA, and CRISPR/Cas9 gene editing approaches were used to target cellular proteins HDAC6 and PKCγ and examine their roles in cell death. Cell viability, RT-qPCR, and Western blotting assays were performed in cysteine-independent tumor cells to examine the anticancer effects of combined tubacin and cysteine deprivation treatment. ResultsWe found that TNBC has differential death responses to cysteine deprivation and the cysteine-dependence of TNBC corelates with the expression levels of claudin genes in addition to the classical EMT markers. To overcome drug resistance in claudin-high/cysteine-independent breast tumor cells, HDAC6 inhibitors were identified by the epigenetic compound library screening as potent sensitizers that synergize with cysteine deprivation to eradicate cysteine-independent tumor cells. Unexpectedly, HDAC6 knockout did not recapitulate the HDAC6 inhibitors-mediated synthetic lethality, indicating that HDAC6 is not the actual target of HDAC6 inhibitors in this context. Transcriptomic profiling revealed that HDAC6 inhibitors synergizes with cysteine depletion to trigger a profound gene transcriptional program. Notably, a zinc-related gene response was observed to accompany with a prominent increase of labile zinc in cells during cell death. We further showed that activation of PKCγ signaling is required to interfere cellular zinc homeostasis and drive HDAC6 inhibitors-mediated cell death.ConclusionOur study demonstrated that HDAC6 inhibitors function as potent sensitizers to overcome the resistance of cysteine deprivation in claudin-high breast tumor cells. Identification of such sensitizers would make the targeted cysteine-dependence therapy applicable in various subtypes of breast cancer.

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HDAC6 Plays a Noncanonical Role in the Regulation of Antitumor Immune Responses, Dissemination, and Invasiveness of Breast Cancer

Cited by 40 publications

References 62 publications

Epigenetic modulation of antitumor immunity for improved cancer immunotherapy

Epigenetic modulation of antitumor immunity for improved cancer immunotherapy

Targeting Macrophages as a Therapeutic Option in Coronavirus Disease 2019

HDAC6 Inhibitors Sensitize Claudin-high Breast Cancer Cells to Cysteine Depletion via Activation of PKCγ Signaling

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HDAC6 Plays a Noncanonical Role in the Regulation of Antitumor Immune Responses, Dissemination, and Invasiveness of Breast Cancer

Cited by 40 publications

References 62 publications

Epigenetic modulation of antitumor immunity for improved cancer immunotherapy

Epigenetic modulation of antitumor immunity for improved cancer immunotherapy

Targeting Macrophages as a Therapeutic Option in Coronavirus Disease 2019

HDAC6&nbsp;Inhibitors Sensitize Claudin-high Breast Cancer Cells to Cysteine Depletion via Activation of PKCγ&nbsp;Signaling

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HDAC6 Inhibitors Sensitize Claudin-high Breast Cancer Cells to Cysteine Depletion via Activation of PKCγ Signaling