Expression of DNA Translesion Synthesis Polymerase η in Head and Neck Squamous Cell Cancer Predicts Resistance to Gemcitabine and Cisplatin-Based Chemotherapy

Zhou, Wendi; Chen, Yih Wen; Liu, Xiyong; Chu, Peiguo; Loria, Sofia; Wang, Yafan; Yen, Yun; Chou, Kai Ming

doi:10.1371/journal.pone.0083978

Cited by 58 publications

(53 citation statements)

References 51 publications

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“…Cisplatin treatment efficacy is inversely correlated to the expression level of Pol η in various cancers (30)(31)(32). To determine whether Pol η down-regulation affects the efficacy of cisplatin treatment in ovarian cancers, we established a 2008 cell line with Pol η stable knockdown and generated xenografts by injecting cells s.c. into Athymic nude mice.…”

Section: Cd117mentioning

confidence: 99%

Enhanced expression of DNA polymerase eta contributes to cisplatin resistance of ovarian cancer stem cells

Srivastava¹,

Han²,

Zhao³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

161

159

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Cancer stem cells (CSCs) with enhanced tumorigenicity and chemoresistance are believed to be responsible for treatment failure and tumor relapse in ovarian cancer patients. However, it is still unclear how CSCs survive DNA-damaging agent treatment. Here, we report an elevated expression of DNA polymerase η (Pol η) in ovarian CSCs isolated from both ovarian cancer cell lines and primary tumors, indicating that CSCs may have intrinsically enhanced translesion DNA synthesis (TLS). Down-regulation of Pol η blocked cisplatin-induced CSC enrichment both in vitro and in vivo through the enhancement of cisplatin-induced apoptosis in CSCs, indicating that Pol η-mediated TLS contributes to the survival of CSCs upon cisplatin treatment. Furthermore, our data demonstrated a depletion of miR-93 in ovarian CSCs. Enforced expression of miR-93 in ovarian CSCs reduced Pol η expression and increased their sensitivity to cisplatin. Taken together, our data suggest that ovarian CSCs have intrinsically enhanced Pol η-mediated TLS, allowing CSCs to survive cisplatin treatment, leading to tumor relapse. Targeting Pol η, probably through enhancement of miR-93 expression, might be exploited as a strategy to increase the efficacy of cisplatin treatment.

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Section: Cd117mentioning

confidence: 99%

Enhanced expression of DNA polymerase eta contributes to cisplatin resistance of ovarian cancer stem cells

Srivastava¹,

Han²,

Zhao³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

161

159

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“…It is not clear from the available literature whether patients with XP-V are prone to the development of obesity and the metabolic syndrome. Given that variation in the expression level of the XP-V gene affects the sensitivity to DNA-damaging agents in various tissues (10,(38)(39)(40), an epidemiological study will be necessary to examine the correlation between the pol η expression level and the metabolic syndrome. In addition to pol η, other translesion synthesis polymerases have been shown to handle various types of DNA lesions (41), and it will be interesting to determine whether KO mice for other lesion bypass polymerases are prone to obesity and metabolic abnormalities.…”

Section: Impact Of Pol η On Cellular Senescence and Adipogenesis Usingmentioning

confidence: 99%

Ablation of XP-V gene causes adipose tissue senescence and metabolic abnormalities

Chen

Harris

Hatahet

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

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Obesity and the metabolic syndrome have evolved to be major health issues throughout the world. Whether loss of genome integrity contributes to this epidemic is an open question. DNA polymerase η (pol η), encoded by the xeroderma pigmentosum (XP-V) gene, plays an essential role in preventing cutaneous cancer caused by UV radiation-induced DNA damage. Herein, we demonstrate that pol η deficiency in mice (pol η −/− ) causes obesity with visceral fat accumulation, hepatic steatosis, hyperleptinemia, hyperinsulinemia, and glucose intolerance. In comparison to WT mice, adipose tissue from pol η −/− mice exhibits increased DNA damage and a greater DNA damage response, indicated by upregulation and/or phosphorylation of ataxia telangiectasia mutated (ATM), phosphorylated H 2 AX (γH 2 AX), and poly[ADP-ribose] polymerase 1 (PARP-1). Concomitantly, increased cellular senescence in the adipose tissue from pol η −/− mice was observed and measured by up-regulation of senescence markers, including p53, p16 Ink4a , p21, senescence-associated (SA) β-gal activity, and SA secretion of proinflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) as early as 4 wk of age. Treatment of pol η −/− mice with a p53 inhibitor, pifithrin-α, reduced adipocyte senescence and attenuated the metabolic abnormalities. Furthermore, elevation of adipocyte DNA damage with a high-fat diet or sodium arsenite exacerbated adipocyte senescence and metabolic abnormalities in pol η −/− mice. In contrast, reduction of adipose DNA damage with N-acetylcysteine or metformin ameliorated cellular senescence and metabolic abnormalities. These studies indicate that elevated DNA damage is a root cause of adipocyte senescence, which plays a determining role in the development of obesity and insulin resistance.T he human genome is constantly challenged by exogenous and endogenous DNA damaging agents. To ensure genome integrity, human cells have faithful DNA replication machinery and DNA repair systems that are coordinated by DNA damage response networks. In response to different extents or types of DNA lesions, the DNA damage response activates appropriate cellular responses, including transient or permanent (senescence) cell cycle arrest, or apoptosis, to minimize the detrimental effects of DNA lesions (1). Reduction or deficiency in DNA repair/replication enzyme activity is well documented to increase vulnerability for the development of cancer, neurodegenerative diseases, and aging (2). In addition, defective DNA repair enzymes are associated with the metabolic symptom; for example, DNA glycosylase (Neil1)-and OGG1-deficient mice are obese (3-5), and nucleotide excision repair protein ERCC1-XPF deficiency causes lipodystrophy (6). Furthermore, DNA damage response protein ataxia telangiectasia mutated (ATM) suppresses JNK activity through p53 signaling and mediates an antioxidant action that has been suggested to be relevant to the metabolic syndrome (7). Nucleotide excision repair XP-A protein may affect metabolism by altering mitochondrial...

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“…Using a nanoparticle-based platform engineered to codeliver cisplatin and Rev1/Rev3-specific siRNAs, Xu et al demonstrated synergistic inhibition of tumor growth in a human prostate cancer xenograft model [95]. Pol η expression was found to be elevated in 67% of head and neck cancers compared to normal tissue [96]. Alterations in Pol η expression have been correlated with response to platinum based chemotherapy.…”

Section: Fa/brca/hrr/tls Crosstalk and Chemoresistancementioning

confidence: 99%

“…Alterations in Pol η expression have been correlated with response to platinum based chemotherapy. Low levels of Polη have been associated with better prognosis, and its expression status considered as a potential marker for platinum therapy effectiveness [96]. The involvement of TLS polymerases in chemoresistance offers further proof that error-prone polymerases are crucial for filling gaps caused by chemotherapeutic drugs, thus providing a novel framework for development of therapeutics with chemosensitization potential.…”

Section: Fa/brca/hrr/tls Crosstalk and Chemoresistancementioning

confidence: 99%

Crosstalk between translesion synthesis, Fanconi anemia network, and homologous recombination repair pathways in interstrand DNA crosslink repair and development of chemoresistance

Haynes

Saadat

Myung

et al. 2015

Mutation Research/Reviews in Mutation Research

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Bifunctional alkylating and platinum based drugs are chemotherapeutic agents used to treat cancer. These agents induce DNA adducts via formation of intrastrand or interstrand (ICL) DNA crosslinks, and DNA lesions of the ICL type are particularly toxic as they block DNA replication and/or DNA transcription. However, the therapeutic efficacies of these drugs are frequently limited due to the cancer cell’s enhanced ability to repair and tolerate these toxic DNA lesions. This ability to tolerate and survive the DNA damage is accomplished by a set of specialized low fidelity DNA polymerases called translesion synthesis (TLS) polymerases since high fidelity DNA polymerases are unable to replicate the damaged DNA template. TLS is a crucial initial step in ICL repair as it synthesizes DNA across the lesion thus preparing the damaged DNA template for repair by the homologous recombination (HR) pathway and Fanconi anemia (FA) network, processes critical for ICL repair. Here we review the molecular features and functional roles of TLS polymerases, discuss the collaborative interactions and cross-regulation of the TLS DNA damage tolerance pathway, the FA network and the BRCA-dependent HRR pathway, and the impact of TLS hyperactivation on development of chemoresistance. Finally, since TLS hyperactivation results from overexpression of Rad6/Rad18 ubiquitinating enzymes (fundamental components of the TLS pathway), increased PCNA ubiquitination, and/or increased recruitment of TLS polymerases, the potential benefits of selectively targeting critical components of the TLS pathway for enhancing anti-cancer therapeutic efficacy and curtailing chemotherapy-induced mutagenesis are also discussed.

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Expression of DNA Translesion Synthesis Polymerase η in Head and Neck Squamous Cell Cancer Predicts Resistance to Gemcitabine and Cisplatin-Based Chemotherapy

Cited by 58 publications

References 51 publications

Enhanced expression of DNA polymerase eta contributes to cisplatin resistance of ovarian cancer stem cells

Enhanced expression of DNA polymerase eta contributes to cisplatin resistance of ovarian cancer stem cells

Ablation of XP-V gene causes adipose tissue senescence and metabolic abnormalities

Crosstalk between translesion synthesis, Fanconi anemia network, and homologous recombination repair pathways in interstrand DNA crosslink repair and development of chemoresistance

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