Histone Deacetylase Inhibition in Non-small Cell Lung Cancer: Hype or Hope?

Mamdani, Hirva; Jalal, Shadia I.

doi:10.3389/fcell.2020.582370

Cited by 59 publications

(43 citation statements)

References 92 publications

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“…Numerous studies indicated that IFIT2, a tumor suppressor gene, inhibited tumor growth, metastasis and induced cell apoptosis in many cancers like oral squamous carcinoma, colorectal cancer, leukemia, osteosarcoma and hepatocellular carcinoma [24]. In present study, we found that high expression of HDAC5, as well as low expression of P300 in glioma cells, decreased acetylation of IFIT2, then upregulated its ubiquitination and degradation, consequently promoting growth, metastasis and stemness of glioma.…”

Section: Discussionsupporting

confidence: 56%

Deacetylation of IFIT2 mediated by HDAC5 promotes the stemness and progression of glioma

Liu

Zhang

Peng

et al. 2021

Preprint

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Background: Glioma is the most common primary brain tumor, and the tumor stemness is a major regulatory factor affecting the progression, metastasis and recurrence of glioma. Recent research has shown that, nonhistone acetylation is widely involved in key cellular processes, including stemness regulation. The deacetylase inhibitors are promising new drugs, but their application and molecular mechanism in glioma have not been elucidated. Methods: CCK8 and colony formation assay were used to detect cell proliferation, transwell assay was used to detect cell migration, flow cytometry was used to analyze cell apoptosis, sphere formation assay and western blot were used to detect the status of stemness. RNA-sequence, quantitative PCR and western blot were performed to screen the key molecules mediating LBH589 function. Immunoprecipitation (IP) and western blot were used to analyze the acetylation level of IFIT2. The SiRNA target HDAC4 or HDAC5, overexpression plasmids of acetyltransferases were used to identify the acetyltransferase and deacetylase regulating IFIT2. The regulatory mechanism was explored by IP and ubiquitination analysis. Finally, the xenograft tumor model in nude mice was constructed and further analyzed in vivo. Results: The data showed that IFIT2 mediates the HDACi LBH589 inhibition on cell proliferation, migration and stemness, and contribution to autophagy and apoptosis in glioma. And the down-regulation of IFIT2 in glioma was confirmed to be related to its deacetylation by overexpression HDAC5, which promotes the stemness and progression of glioma. Further, deacetylation of IFIT2 by HDAC5 was demonstrated to induce its ubiquitination and subsequent protein instability, which led to loss of anti-tumor activity for IFIT2, and acceleration to glioma stemness and progression. In addition, the results indicated that IFIT2 inhibits PKC pathway, and suppressing of IFIT2 promotes tumor growth in vivo. Conclusions: These results not only clarify a novel post-transcriptional regulatory mode of IFIT2, but also provide a new sight of molecular mechanism for HDACi in glioma.

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Section: Discussionsupporting

confidence: 56%

Deacetylation of IFIT2 mediated by HDAC5 promotes the stemness and progression of glioma

Liu

Zhang

Peng

et al. 2021

Preprint

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“…The authors proposed that cytoplasm-localized SIRT1 downregulation may represent a novel therapeutic target to inhibit cisplatin resistance in cisplatin-resistant NSCLC cells ( 108 ). A review of the topic of histone deacetylase inhibition in NSCLC indicated that a SIRT1-mediated survival advantage may represent another mechanism through which NSCLC cells develop resistance to EGFR-TKIs ( 109 ), possibly through mediated by regulating the oxidative phosphorylation of mitochondria in lung adenocarcinoma cells, and then selectively eliminating TKI-resistant cancer stem cells.…”

Section: The Association Of Sirt1 With Hypoxia-induced Chemoresistance In Nsclcmentioning

confidence: 99%

SIRT1/PGC-1α/PPAR-γ Correlate With Hypoxia-Induced Chemoresistance in Non-Small Cell Lung Cancer

Luo

et al. 2021

Front. Oncol.

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Resistance is the major cause of treatment failure and disease progression in non-small cell lung cancer (NSCLC). There is evidence that hypoxia is a key microenvironmental stress associated with resistance to cisplatin, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), and immunotherapy in solid NSCLCs. Numerous studies have contributed to delineating the mechanisms underlying drug resistance in NSCLC; nevertheless, the mechanisms involved in the resistance associated with hypoxia-induced molecular metabolic adaptations in the microenvironment of NSCLC remain unclear. Studies have highlighted the importance of posttranslational regulation of molecular mediators in the control of mitochondrial function in response to hypoxia-induced metabolic adaptations. Hypoxia can upregulate the expression of sirtuin 1 (SIRT1) in a hypoxia-inducible factor (HIF)-dependent manner. SIRT1 is a stress-dependent metabolic sensor that can deacetylate some key transcriptional factors in both metabolism dependent and independent metabolic pathways such as HIF-1α, peroxisome proliferator-activated receptor gamma (PPAR-γ), and PPAR-gamma coactivator 1-alpha (PGC-1α) to affect mitochondrial function and biogenesis, which has a role in hypoxia-induced chemoresistance in NSCLC. Moreover, SIRT1 and HIF-1α can regulate both innate and adaptive immune responses through metabolism-dependent and -independent ways. The objective of this review is to delineate a possible SIRT1/PGC-1α/PPAR-γ signaling-related molecular metabolic mechanism underlying hypoxia-induced chemotherapy resistance in the NSCLC microenvironment. Targeting hypoxia-related metabolic adaptation may be an attractive therapeutic strategy for overcoming chemoresistance in NSCLC.

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“…Combining coexpression analysis and the CMap database, we identified four small-molecule drugs which might facilitate the treatment of LUAD, including quinostatin, MS-275, daunorubicin, and menadione. Clinical trials have explored the use of MS-275, a histone deacetylase inhibitor (HDACi), to reverse drug resistance and enhance clinical efficacy (43), while menadione (vitamin k3) is widely used in the treatment of coagulation disorders. Recent studies have reported that menadione reduced the risk of cancer through antiproliferative, autophagic, and proapoptotic effects (44,45).…”

Section: Discussionmentioning

confidence: 99%