Distinct Subpopulations of Head and Neck Cancer Cells with Different Levels of Intracellular Reactive Oxygen Species Exhibit Diverse Stemness, Proliferation, and Chemosensitivity

Chang, Ching Wen; Chen, Yu Syuan; Chou, Shiu Huey; Han, Chia Li; Chen, Yu‐Ju; Yang, Cheng Chieh; Huang, Chih Yang; Lo, Jeng‐Fan

doi:10.1158/0008-5472.can-14-0626

Cited by 103 publications

(88 citation statements)

References 52 publications

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“…S1C) and tumor sphereforming ability ( Supplementary Fig. S1D), which are typical signs of stem-like population enriched in drug-resistant cells (26). In addition, G9a and the corresponding H3K9 methylations are higher expressed in CR cells than the parental cells (Fig.…”

Section: G9a Expression Is Associated With Poor Chemotherapeutic Respmentioning

confidence: 90%

Histone Methyltransferase G9a Drives Chemotherapy Resistance by Regulating the Glutamate–Cysteine Ligase Catalytic Subunit in Head and Neck Squamous Cell Carcinoma

Liu

Hua

et al. 2017

Molecular Cancer Therapeutics

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Transient chemotherapeutic response is a major obstacle to treating head and neck squamous cell carcinomas (HNSCC). Histone methyltransferase G9a has recently been shown to be abundantly expressed in HNSCC, and is required to maintain the malignant phenotype. In this study, we found that high G9a expression is significantly associated with poor chemotherapeutic response and disease-free survival in HNSCC patients. Similarly, G9a expression and enzymatic activity were elevated in cisplatinresistant HNSCC cells. Genetic or pharmacologic inhibition of G9a sensitized the resistant cells to cisplatin, increasing cellular apoptosis. Mechanistic investigations indicated that G9a contributes to transcriptional activation of the glutamate-cysteine ligase catalytic subunit (GCLC), which results in upregulation of cellular glutathione (GSH) and drug resistance. In addition, we observed a significant positive correlation between G9a and GCLC expression in tumors of HNSCC patients. Taken together, our findings provide evidence that G9a protects HNSCC cells against chemotherapy by increasing the synthesis of GSH, and imply G9a as a promising target for overcoming cisplatin resistance in HNSCC.

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Section: G9a Expression Is Associated With Poor Chemotherapeutic Respmentioning

confidence: 90%

Histone Methyltransferase G9a Drives Chemotherapy Resistance by Regulating the Glutamate–Cysteine Ligase Catalytic Subunit in Head and Neck Squamous Cell Carcinoma

Liu

Hua

et al. 2017

Molecular Cancer Therapeutics

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“…Similarly, ROS low cells in head and neck cancers express CSC markers and have enhanced tumor-initiating capacity. ROS low cells are enriched after cisplatin treatment and inhibition of antioxidant systems in these cells sensitizes them to the drug (46). Aldehyde dehydrogenase (ALDH) proteins can function as antioxidants by controlling the oxidation of a variety of aldehydes, including toxic byproducts generated by ROS (47).…”

Section: Metabolic Heterogeneitymentioning

confidence: 99%

Intratumoral Heterogeneity: From Diversity Comes Resistance

Pribluda¹,

Cruz²,

Jackson³

2015

Clinical Cancer Research

122

102

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Tumors consist of a heterogeneous mixture of functionally distinct cancer cells. These functional differences can be caused by varying levels of receptor activity, differentiation, and distinct metabolic and epigenetic states. Intratumoral heterogeneity can lead to interdependence among different subpopulations of cells for sustained tumor growth. In addition, subpopulations can vary widely in their responses to therapeutic agents. As such, it is believed that intratumoral heterogeneity may underlie incomplete treatment responses, acquired and innate resistance, and disease relapse observed in the clinic in response to conventional chemotherapy and targeted agents. Clin Cancer Res; 21(13); 2916-23.Ó2015 AACR.

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“…However, recent evidence showed that the upregulation of antioxidant protein Nrf2 might promote survival and resistance to therapies in cancer cells (34). A subpopulation of HNSCC cells carrying low ROS may exhibit more stemness and chemoresistance properties (35).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-211 Enhances the Oncogenicity of Carcinogen-Induced Oral Carcinoma by Repressing TCF12 and Increasing Antioxidant Activity

Chen¹,

et al. 2016

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miR-211 expression in human oral squamous cell carcinoma (OSCC) has been implicated in poor patient survival. To investigate the oncogenic roles of miR-211, we generated K14-EGFPmiR-211 transgenic mice tagged with GFP. Induction of oral carcinogenesis in transgenic mice using 4-nitroquinoline 1-oxide (4NQO) resulted in more extensive and severe tongue tumorigenesis compared with control animals. We found that 4NQO and arecoline upregulated miR-211 expression in OSCC cells. In silico and experimental evidence further revealed that miR-211 directly targeted transcription factor 12 (TCF12), which mediated suppressor activities in OSCC cells and was drastically downregulated in tumor tissues. We used GeneChip analysis and bioinformatic algorithms to identify transcriptional targets of TCF12 and confirmed through reporter and ChIP assays that family with sequence similarity 213, member A (FAM213A), a peroxiredoxin-like antioxidative protein, was repressed transcriptionally by TCF12. FAM213A silencing in OSCC cells diminished oncogenic activity, reduced the ALDH1-positive cell population, and increased reactive oxygen species. TCF12 and FAM213A expression was correlated inversely in head and neck carcinoma samples according to The Cancer Genome Atlas. OSCC patients bearing tumors with high FAM213A expression tended to have worse survival. Furthermore, 4NQO treatment downregulated TCF12 and upregulated FAM213A by modulating miR-211 both in vitro and in vivo. Overall, our findings develop a mouse model that recapitulates the molecular and histopathologic alterations of human OSCC pathogenesis and highlight a new miRNA-mediated oncogenic mechanism. Cancer Res; 76(16); 4872-86. Ó2016 AACR.

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Distinct Subpopulations of Head and Neck Cancer Cells with Different Levels of Intracellular Reactive Oxygen Species Exhibit Diverse Stemness, Proliferation, and Chemosensitivity

Abstract: Head and neck squamous cell carcinoma (HNSCC) is driven by cancer-initiating cells (CIC)

Cited by 103 publications

References 52 publications

Histone Methyltransferase G9a Drives Chemotherapy Resistance by Regulating the Glutamate–Cysteine Ligase Catalytic Subunit in Head and Neck Squamous Cell Carcinoma

Histone Methyltransferase G9a Drives Chemotherapy Resistance by Regulating the Glutamate–Cysteine Ligase Catalytic Subunit in Head and Neck Squamous Cell Carcinoma

Intratumoral Heterogeneity: From Diversity Comes Resistance

MicroRNA-211 Enhances the Oncogenicity of Carcinogen-Induced Oral Carcinoma by Repressing TCF12 and Increasing Antioxidant Activity

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