Targeting histone deacetylase SIRT1 selectively eradicates EGFR TKI-resistant cancer stem cells via regulation of mitochondrial oxidative phosphorylation in lung adenocarcinoma

Sun, Jing; Li, Guifang; Liu, Yiwen; Ma, Mingyang; Song, Kaifang; Li, Huaxu; Zhu, Daxing; Tang, Xiaojun; Kong, Jinyu; Yuan, Xiang

doi:10.1016/j.neo.2019.10.006

Cited by 20 publications

(27 citation statements)

References 36 publications

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“…Consequently, administration of a SIRT1 inhibitor tenovin6 (TV6) in combination with gefitinib showed tumor regression in resistant xenograft models. Additionally, co-administration of TV6 leads to decrease in the dose of gefitinib necessary to induce tumor response in preclinical models ( Sun et al, 2020 ). A phase I/II trial enrolled 132 patients with advanced EGFR mutant NSCLC and randomized them to erlotinib plus entinostat or erlotinib plus placebo ( Witta et al, 2012 ).…”

Section: Clinical Utility Of Hdaci In Nsclcmentioning

confidence: 99%

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

Mamdani

Jalal

2020

Front. Cell Dev. Biol.

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Epigenetic modulation, including acetylation, methylation, phosphorylation, and ubiquitination, plays a pivotal role in regulation of gene expression. Histone acetylation—a balance between the activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs)—is one of the key epigenetic events. Our understanding of the role of HDACs in cancer is evolving. A number of HDAC isoenzymes are overexpressed in a variety of malignancies. Aberrant histone acetylation is associated with dysregulation of tumor suppressor genes leading to development of several solid tumors and hematologic malignancies. Pre-clinical studies have demonstrated that HDAC-1 gene expression is associated with lung cancer progression. Histone hypoacetylation is associated with more aggressive phenotype in adenocarcinoma of the lung. HDAC inhibitors (HDACi) have pleiotropic cellular effects and induce the expression of pro-apoptotic genes/proteins, cause cellular differentiation and/or cell cycle arrest, inhibit angiogenesis, and inhibit transition to a mesenchymal phenotype. Consequently, treatment with HDACi has shown anti-proliferative activity in non-small cell lung cancer (NSCLC) cell lines. Despite promising results in pre-clinical studies, HDACi have shown only modest single agent activity in lung cancer clinical trials. HDAC activation has been implicated as one of the mechanisms causing resistance to chemotherapy, molecularly targeted therapy, and immune checkpoint inhibition. Therefore, there is a growing interest in combining HDACi with these agents to enhance their efficacy or reverse resistance. In this paper, we review the available preclinical and clinical evidence for the use of HDACi in NSCLC. We also review the challenges precluding widespread clinical utility of HDACi as a cancer therapy and future directions.

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Section: Clinical Utility Of Hdaci In Nsclcmentioning

confidence: 99%

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

Mamdani

Jalal

2020

Front. Cell Dev. Biol.

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“…CSCs have the characteristics of carcinogenicity, multiple differentiation and self-renewal. Some scholars believe that tumor recurrence, metastasis and resistance to radiotherapy and chemotherapy were due to the existence of tumor stem cells [10]. The rst solid tumor to prove the existence of CSCs was BC; Al-Hajj et al proved that CD44 + /CD24 − /(low)-lineage cells isolated from BC tissue can form tumors in immunode cient mice [25].…”

Section: Discussionmentioning

confidence: 99%

PiRNA MW557525 Promotes the Vitality and Pluripotency of Piwil2-iCSCs by Regulating NOP56.

Zhang

Wang

Tan

et al. 2021

Preprint

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Objective Cancer stem cells (CSCs) play an important role in tumor development. Some studies have demonstrated that P-element–induced wimpy testis (Piwi)–interacting ribonucleic acids (piRNAs) participate in the progression of various cancers. However, the detailed function of piRNAs in CSCs requires further investigation. The aim of the present study was to investigate the effect of the uknown upregulated piRNA MW557525 and its predicted target gene nucleolar protein 56 (NOP56) inPiwi-like protein 2 (Piwil2)–induced CSCs (Piwil2-iCSCs).Methods We screened differential piRNAs of Piwil2-iCSCs using high-throughput sequencing (HTS). Target genes were predicted by the miRanda algorithm and subjected to Gene Ontology (GO) analysis. One of the differential piRNAs, MW557525, and its target gene NOP56 were transfected and silenced in Piwil2-iCSCs, respectively. Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to detect expression levels of piRNA MW557525 and NOP56 in Piwil2-iCSCs after transfection. We measured protein levels of NOP56 in different groups via Western blot (WB), verified interactions using a dual luciferase reporter assay (LRA) and investigated the effect of piRNA MW557525 and NOP56 on Piwil2-iCSC proliferation using a Cell Counting Kit-8 (CCK-8). In addition, we evaluated cell migratory and invasive abilities via transwell assay and detected cell apoptotic ability via flow cytometry (FCM) assay. Protein levels of Cluster of Differentiation 24 (CD24), CD133, Krüppel-like factor 4 (KLF4) and sex-determining region Y–related high-mobility group (HMG) box 12 (SOX2) were measured to evaluate the change in Piwil2-iCSC pluripotency after transfection.Results Via HTS, we screened out 204 differential piRNAs, and miRanda predicted 77 target genes. GO analysis showed that the biological processes (BPs) of these target genes were mainly involved in regulating the calcium concentration of cells and their molecular functions (MFs) were mainly involved in ATPase activity.The expression of piRNA MW557525 and NOP56 were significantly upregulated,and piRNA MW557525 was negatively associated with NOP56 in Piwil2-iCSCs. PiRNA MW557525 promoted proliferation, migration, invasion and pluripotency and inhibited apoptosis, while NOP56 suppressed proliferation, migration, invasion and pluripotency and induced apoptosis, in Piwil2-iCSCs.Conclusion Taken together, these findings suggested that piRNA MW557525 promoted and maintained the vitality and pluripotency of Piwil2-iCSCs, while NOP56 inhibited these characteristics. Therefore, piRNA MW557525 might be a novel therapeutic target in Piwil2-iCSCs.

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“…T315I is the most frequent mutation causing imatinib resistance in patients with advanced CML or Ph + acute lymphocytic leukemia ( 43 ). It has been demonstrated that targeting Sphk1 and SIRT1 individually enhanced the sensitivity to TKI in various cancer cells, including acute myeloid leukemia, CML, renal cancer and lung adenocarcinoma ( 25 , 27 , 44 , 45 ), indicated its potential as a novel agent for the treatment of TKI-resistant leukemia. The present study lacked data on the treatment for leukemia cells with TKI in combination with SKI-II and EX527.…”

Section: Discussionmentioning

confidence: 99%

Combined effects on leukemia cell growth by targeting sphingosine kinase 1 and sirtuin 1 signaling

Gao

Liu

et al. 2020

Exp Ther Med

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Targeting multiple signaling pathways is a potential novel therapeutic strategy for the treatment of leukemias. Leukemia cells express high levels of sphingosine kinase 1 (Sphk1) and sirtuin 1 (SIRT1). However, to the best of our knowledge, their interaction and potential synergistic inhibitory effects on the growth and survival of leukemia cells have not been investigated. The present study revealed the role of the Sphk1/S1P/SIRT1 axis in K562, KCL22 and TF1 cells and hypothesized that the inhibition of Sphk1 and SIRT1 had synergistic effects on the growth and survival of leukemia cells. Cell viability was tested using a Cell Counting Kit-8 assay and cell colony forming assay. Cell apoptosis was detected using Annexin V-APC/PI staining. The stages of the cell cycle were measured using PI staining. Protein levels were measured by western blotting. Treatment of leukemia cells with S1P resulted in the upregulation of SIRT1 expression, whereas inhibition of Sphk1 induced SIRT1 downregulation in leukemia cells. Both SKI-II and EX527 actively suppressed growth, blocked cell cycle progression and induced apoptosis of leukemia cells. Furthermore, inhibition of Sphk1 and SIRT1 exhibited suppressive effects on the growth and survival of leukemia cells. Notably, the inhibition of Sphk1 and SIRT1 suppressed cell growth and induced apoptosis of T-315I mutation-harboring cells. Additionally, treatment with SKI-II and EX527 suppressed the ERK and STAT5 pathways in leukemia cells. These data indicated that targeting the Sphk1/S1P/SIRT1 axis may be a novel therapeutic strategy for the treatment of leukemia.

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Targeting histone deacetylase SIRT1 selectively eradicates EGFR TKI-resistant cancer stem cells via regulation of mitochondrial oxidative phosphorylation in lung adenocarcinoma

Cited by 20 publications

References 36 publications

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

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

PiRNA MW557525 Promotes the Vitality and Pluripotency of Piwil2-iCSCs by Regulating NOP56.

Combined effects on leukemia cell growth by targeting sphingosine kinase 1 and sirtuin 1 signaling

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