RECQL1 DNA Repair Helicase: A Potential Therapeutic Target and a Proliferative Marker against Ovarian Cancer

Sanada, Sakiko; Futami, Kazunobu; Terada, Atsumu; Yonemoto, Koji; Ogasawara, Satoshi; Akiba, Jun; Yasumoto, Makiko; Sumi, Akiko; Ushijima, Kimio; Kamura, Toshiharu; Furuichi, Yasuhiro; Yano, Hirohisa

doi:10.1371/journal.pone.0072820

Cited by 21 publications

(27 citation statements)

References 26 publications

(26 reference statements)

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“…Their results suggested that even in unchallenged cancer cells, RECQL1 serves to promote expression of genes that play important roles in cell migration, invasion and metastasis. These results are in line with a previous observation that RECQL1 expression is up-regulated in cancer cell lines compared to normal cells [89], and elevated in certain types of cancers [90–92]. Genes down-regulated upon RECQL1 silencing displayed an enrichment of predicted G4-forming sequences in their promoter elements [88].…”

Section: Human Recq Helicases and Their Roles In Response To Nuclear supporting

confidence: 90%

Mechanistic and biological considerations of oxidatively damaged DNA for helicase-dependent pathways of nucleic acid metabolism

Crouch

Brosh

2017

Free Radical Biology and Medicine

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Cells are under constant assault from reactive oxygen species that occur endogenously or arise from environmental agents. An important consequence of such stress is the generation of oxidatively damaged DNA, which is represented by a wide range of non-helix distorting and helix-distorting bulkier lesions that potentially affect a number of pathways including replication and transcription; consequently DNA damage tolerance and repair pathways are elicited to help cells cope with the lesions. The cellular consequences and metabolism of oxidatively damaged DNA can be quite complex with a number of DNA metabolic proteins and pathways involved. Many of the responses to oxidative stress involve a specialized class of enzymes known as helicases, the topic of this review. Helicases are molecular motors that convert the energy of nucleoside triphosphate hydrolysis to unwinding of structured polynucleic acids. Helicases by their very nature play fundamentally important roles in DNA metabolism and are implicated in processes that suppress chromosomal instability, genetic disease, cancer, and aging. We will discuss the roles of helicases in response to nuclear and mitochondrial oxidative stress and how this important class of enzymes help cells cope with oxidatively generated DNA damage through their functions in the replication stress response, DNA repair, and transcriptional regulation.

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Section: Human Recq Helicases and Their Roles In Response To Nuclear supporting

confidence: 90%

Mechanistic and biological considerations of oxidatively damaged DNA for helicase-dependent pathways of nucleic acid metabolism

Crouch

Brosh

2017

Free Radical Biology and Medicine

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“…On the other hand, established tumours may be dependent on RECQL1 to tolerate replication induced DNA damage, a feature seen in proliferating cancer cells. In fact RECQL1 has been shown to be overexpressed in glioblastoma (31), hepatocellular carcinoma (32), ovarian cancers (33), melanoma (34) and head & neck cancer models (35). Whether RECQL1 also impacts sporadic breast cancer pathogenesis is currently unknown.…”

Section: Discussionmentioning

confidence: 99%

Clinicopathological and Functional Significance of RECQL1 Helicase in Sporadic Breast Cancers

Arora

Parvathaneni

Aleskandarany

et al. 2017

Molecular Cancer Therapeutics

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RECQL1, a key member of the RecQ family of DNA helicases, is required for DNA replication and DNA repair. Two recent studies have shown that germ-line RECQL1 mutations are associated with increased breast cancer susceptibility. Whether altered RECQL1 expression has clinicopathological significance in sporadic breast cancers is unknown. We evaluated RECQL1 at the transcriptomic level [METABRIC cohort, n=1977] and at the protein level [cohort 1, n=897; cohort 2, n= 252; cohort 3 (BRCA-germline deficient), n=74]. In RECQL1-depleted breast cancer cells we investigated anthracycline sensitivity. High RECQL1 mRNA was associated with intClust.3 (p=0.026) which is characterised by low genomic instability. On the other hand, low RECQL1 mRNA was linked to intClust.8 (luminal A ER+ sub-group) (p=0.0455) and intClust.9 (luminal B ER+ sub-group) (p=0.0346) molecular phenotypes. Low RECQL1 expression was associated with shorter breast cancer specific survival (p=0.001). At the protein level, low nuclear RECQL1 level was associated with larger tumour size, lymph node positivity, high tumour grade , high mitotic index, pleomorphism, de-differentiation, ER negativity and HER-2 overexpression (p values<0.05). In ER+ tumours that received endocrine therapy, low RECQL1 was associated with poor survival (p=0.008). However, in ER− negative tumours that received anthracycline based chemotherapy, high RECQL1 was associated with poor survival (p=0.048). In RECQL1-depleted breast cancer cell lines we confirmed doxorubicin sensitivity which was associated with DNA double strand breaks accumulation, S-phase cell cycle arrest and apoptosis. We conclude that RECQL1 has prognostic and predictive significance in breast cancers.

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“…RECQ1 is overexpressed or amplified in rapidly dividing cancer cells (16, 25, 26) and in human cancer tissues (18, 27, 28). RECQ1 knockdown in cancer cells significantly reduces cell migration and invasion (29), and gene expression analysis has shown that RECQ1 actually regulates genes associated with cancer progression (30).…”

Section: Discussionmentioning

confidence: 99%

RECQ1 A159C Polymorphism Is Associated With Overall Survival of Patients With Resected Pancreatic Cancer: A Replication Study in NRG Oncology Radiation Therapy Oncology Group 9704

Moughan

Crane

et al. 2016

International Journal of Radiation Oncology*Biology*Physics

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Purpose To confirm whether a previously observed association between RECQ1 A159C variant and clinical outcome of resectable pancreatic cancer patients treated with preoperative chemoradiation is reproducible in another patient population prospectively treated with postoperative chemoradiation. Methods and Materials Patients were selected, according to tissue availability, from eligible patients with resected pancreatic cancer who were enrolled on the NRG Oncology Radiation Therapy Oncology Group 9704 trial of 5-fluorouacil (5-FU)-based chemoradiation preceded and followed by 5-FU or gemcitabine. Deoxyribonucleic acid was extracted from paraffin-embedded tissue sections, and genotype was determined using the Taqman method. The correlation between genotype and overall survival was analyzed using a Kaplan-Meier plot, log-rank test, and multivariate Cox proportional hazards models. Results In the 154 of the study’s 451 eligible patients with evaluable tissue, genotype distribution followed Hardy-Weinberg equilibrium (ie, 37% had genotype AA, 43% AC, and 20% CC). The RECQ1 variant AC/CC genotype carriers were associated with being node positive compared with the AA carrier (P = .03). The median survival times (95% confidence interval [CI]) for AA, AC, and CC carriers were 20.6 (16.3–26.1), 18.8 (14.2–21.6), and 14.2 (10.3–21.0) months, respectively. On multivariate analysis, patients with the AC/CC genotypes were associated with worse survival than patients with the AA genotype (hazard ratio [HR] 1.54, 95% CI 1.07–2.23, P =.022). This result seemed slightly stronger for patients on the 5-FU arm (n = 82) (HR 1.64, 95% CI 0.99–2.70, P =.055) than for patients on the gemcitabine arm (n = 72, HR 1.46, 95% CI 0.81–2.63, P =.21). Conclusions Results of this study suggest that the RECQ1 A159C genotype may be a prognostic or predictive factor for resectable pancreatic cancer patients who are treated with adjuvant 5-FU before and after 5-FU-based chemoradiation. Further study is needed in patients treated with gemcitabine to determine whether an association exists.

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RECQL1 DNA Repair Helicase: A Potential Therapeutic Target and a Proliferative Marker against Ovarian Cancer

Cited by 21 publications

References 26 publications

Mechanistic and biological considerations of oxidatively damaged DNA for helicase-dependent pathways of nucleic acid metabolism

Mechanistic and biological considerations of oxidatively damaged DNA for helicase-dependent pathways of nucleic acid metabolism

Clinicopathological and Functional Significance of RECQL1 Helicase in Sporadic Breast Cancers

RECQ1 A159C Polymorphism Is Associated With Overall Survival of Patients With Resected Pancreatic Cancer: A Replication Study in NRG Oncology Radiation Therapy Oncology Group 9704

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