Regulators of Global Genome Repair Do Not Respond to DNA Damaging Therapy but Correlate with Survival in Melanoma

Ashton, Katie A.; Vilain, Ricardo E.; Avery‐Kiejda, Kelly A.; Davey, Ryan J.; Murray, Heather C; Budden, Timothy; Braye, Stephen; Zhang, Xu Dong; Hersey, Peter; Scott, Rodney J.

doi:10.1371/journal.pone.0070424

Cited by 8 publications

(2 citation statements)

References 46 publications

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“…To date, somatic mutations in XPC, DDB1 and DDB2 have rarely been reported in melanoma tumours. We reported that upstream regulators of GGR including p53, BRCA1 and PCNA are not responsible [ 18 , 23 , 29 ]. One possible mechanism affecting the expression of these genes is dysregulation of epigenetics such as DNA methylation.…”

Section: Introductionmentioning

confidence: 99%

Sequential decitabine and carboplatin treatment increases the DNA repair protein XPC, increases apoptosis and decreases proliferation in melanoma

Budden

Westhuizen

2018

BMC Cancer

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BackgroundMelanoma has two key features, an over-representation of UV-induced mutations and resistance to DNA damaging chemotherapy agents. Both of these features may result from dysfunction of the nucleotide excision repair pathway, in particular the DNA damage detection branch, global genome repair (GGR). The key GGR component XPC does not respond to DNA damage in melanoma, the cause of this lack of response has not been investigated. In this study, we investigated the role of methylation in reduced XPC in melanoma.MethodsTo reduce methylation and induce DNA-damage, melanoma cell lines were treated with decitabine and carboplatin, individually and sequentially. Global DNA methylation levels, XPC mRNA and protein expression and methylation of the XPC promoter were examined. Apoptosis, cell proliferation and senescence were also quantified. XPC siRNA was used to determine that the responses seen were reliant on XPC induction.ResultsTreatment with high-dose decitabine resulted in global demethylation, including the the shores of the XPC CpG island and significantly increased XPC mRNA expression. Lower, clinically relevant dose of decitabine also resulted in global demethylation including the CpG island shores and induced XPC in 50% of cell lines. Decitabine followed by DNA-damaging carboplatin treatment led to significantly higher XPC expression in 75% of melanoma cell lines tested. Combined sequential treatment also resulted in a greater apoptotic response in 75% of cell lines compared to carboplatin alone, and significantly slowed cell proliferation, with some melanoma cell lines going into senescence. Inhibiting the increased XPC using siRNA had a small but significant negative effect, indicating that XPC plays a partial role in the response to sequential decitabine and carboplatin.ConclusionsDemethylation using decitabine increased XPC and apoptosis after sequential carboplatin. These results confirm that sequential decitabine and carboplatin requires further investigation as a combination treatment for melanoma.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4010-9) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Sequential decitabine and carboplatin treatment increases the DNA repair protein XPC, increases apoptosis and decreases proliferation in melanoma

Budden

Westhuizen

2018

BMC Cancer

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“…Lower levels of NER post-platinum chemotherapy have been confirmed in ovarian cancer studies including low DDB2 in platinum-resistant ovarian cancer cell lines (Barakat et al 2010) and low XPA in platinum-resistant ovarian cancer tumours (Barakat et al 2010). In addition, low NER and platinum resistance has been reported for several other cancer types including non-small-cell lung cancer, gastric cancer, colorectal cancer and melanoma (Bowden et al 2010(Bowden et al , 2013. NER proteins are a promising area in biomarker development for platinum resistance for use in real-time clinical settings after platinum treatment has concluded.…”

Section: Figurementioning

confidence: 83%

Biomarkers of platinum resistance in ovarian cancer: what can we use to improve treatment

Zyl¹,

Tang²,

Bowden³

2018

Endocrine-Related Cancer

149

116

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Ovarian cancer has poor survival rates due to a combination of diagnosis at advanced disease stages and disease recurrence as a result of platinum chemotherapy resistance. High-grade serous ovarian cancer (HGSOC), the most common ovarian cancer subtype, is conventionally treated with surgery and paclitaxel/carboplatin combination chemotherapy. Initial response rates are 60-80%, but eventually the majority of patients become platinum-resistant with subsequent relapses. Extensive research on individual biomarkers of platinum resistance has revealed many potential targets for the development new treatments. While this is ongoing, there are also epigenetic, DNA repair, genome and immune changes characterised in platinum-resistant HGSOC that can be targeted with current therapies. This review discusses biomarkers of platinum chemotherapy resistance in ovarian cancer with a focus on biomarkers that are targetable with alternative treatment combinations to those currently used. After decades of research focused on elucidating the biological cause of platinum resistance, future research needs to focus on using this knowledge to overcome resistance for patients with ovarian cancer.

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Nucleotide excision repair: Why is it not used to predict response to platinum-based chemotherapy?

Bowden¹

2014

Cancer Letters

124

133

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Regulators of Global Genome Repair Do Not Respond to DNA Damaging Therapy but Correlate with Survival in Melanoma

Cited by 8 publications

References 46 publications

Sequential decitabine and carboplatin treatment increases the DNA repair protein XPC, increases apoptosis and decreases proliferation in melanoma

Sequential decitabine and carboplatin treatment increases the DNA repair protein XPC, increases apoptosis and decreases proliferation in melanoma

Biomarkers of platinum resistance in ovarian cancer: what can we use to improve treatment

Nucleotide excision repair: Why is it not used to predict response to platinum-based chemotherapy?

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