FANCD2 re-expression is associated with glioma grade and chemical inhibition of the Fanconi Anaemia pathway sensitises gliomas to chemotherapeutic agents

Patil, Abhijit A.; Sayal, Parag; Depondt, Marie-Lise; Beveridge, Ryan; Roylance, Anthony; Kriplani, Deepti H.; Myers, Katie; Cox, Angela; Jellinek, David; Fernando, M. A.; Carroll, Thomas; Collis, Spencer J.

doi:10.18632/oncotarget.2225

Cited by 34 publications

(32 citation statements)

References 29 publications

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“…Other pathways, in turn, are silenced in the transformed cells and tissues [ 37 – 38 ]. Intracellular regulation is also implicated in metastasing, drug resistance and tumor invasiveness [ 39 – 42 ]. We propose that the current bioinformatic approach based on the OncoFinder algorithm opens broad perspectives for finding tight associations of signaling pathway activation with the prognosis of disease progression and with the efficiency of anticancer treatment.…”

Section: Resultsmentioning

confidence: 99%

Signaling pathways activation profiles make better markers of cancer than expression of individual genes

et al. 2014

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Identification of reliable and accurate molecular markers remains one of the major challenges of contemporary biomedicine. We developed a new bioinformatic technique termed OncoFinder that for the first time enables to quantatively measure activation of intracellular signaling pathways basing on transcriptomic data. Signaling pathways regulate all major cellular events in health and disease. Here, we showed that the Pathway Activation Strength (PAS) value itself may serve as the biomarker for cancer, and compared it with the “traditional” molecular markers based on the expression of individual genes. We applied OncoFinder to profile gene expression datasets for the nine human cancer types including bladder cancer, basal cell carcinoma, glioblastoma, hepatocellular carcinoma, lung adenocarcinoma, oral tongue squamous cell carcinoma, primary melanoma, prostate cancer and renal cancer, totally 292 cancer and 128 normal tissue samples taken from the Gene expression omnibus (GEO) repository. We profiled activation of 82 signaling pathways that involve ~2700 gene products. For 9/9 of the cancer types tested, the PAS values showed better area-under-the-curve (AUC) scores compared to the individual genes enclosing each of the pathways. These results evidence that the PAS values can be used as a new type of cancer biomarkers, superior to the traditional gene expression biomarkers.

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Section: Resultsmentioning

confidence: 99%

Signaling pathways activation profiles make better markers of cancer than expression of individual genes

et al. 2014

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“…As the inhibition of HDAC1/2/3 downregulates RAD51 and FANCD2, and both protect cancer cells against temozolomide (15,39) because of their role in HR (13,40), the effect of HDACi on HR was assayed. Inhibition of class I HDACs significantly decreased HR activity in both D05 and A375 melanoma cell lines upon DSB induction (Fig.…”

Section: Inhibition Of Hdac1/2/3 Downregulates Rad51 and Fancd2mentioning

confidence: 99%

Enhanced Histone Deacetylase Activity in Malignant Melanoma Provokes RAD51 and FANCD2-Triggered Drug Resistance

et al. 2016

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DNA-damaging anticancer drugs remain a part of metastatic melanoma therapy. Epigenetic reprogramming caused by increased histone deacetylase (HDAC) activity arising during tumor formation may contribute to resistance of melanomas to the alkylating drugs temozolomide, dacarbazine, and fotemustine. Here, we report on the impact of class I HDACs on the response of malignant melanoma cells treated with alkylating agents. The data show that malignant melanomas in situ contain a high level of HDAC1/2 and malignant melanoma cells overexpress HDAC1/2/3 compared with noncancer cells. Furthermore, pharmacologic inhibition of class I HDACs sensitizes malignant melanoma cells to apoptosis following exposure to alkylating agents, while not affecting primary melanocytes. Inhibition of HDAC1/2/3 caused sensitization of melanoma cells to temozolomide in vitro and in melanoma xenografts in vivo. HDAC1/2/3 inhibition resulted in suppression of DNA double-strand break (DSB) repair by homologous recombination because of downregulation of RAD51 and FANCD2. This sensitized cells to the cytotoxic DNA lesion O 6 -methylguanine and caused a synthetic lethal interaction with the PARP-1 inhibitor olaparib. Furthermore, knockdown experiments identified HDAC2 as being responsible for the regulation of RAD51. The influence of class I HDACs on DSB repair by homologous recombination and the possible clinical implication on malignant melanoma therapy with temozolomide and other alkylating drugs suggests a combination approach where class I HDAC inhibitors such as valproic acid or MS-275 (entinostat) appear to counteract HDAC-and RAD51/FANCD2-mediated melanoma cell resistance. Cancer Res; 76(10); 3067-77. Ó2016 AACR.

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“…Furthermore, inhibition of FANCD2 is known to sensitize cancer cells to chemotherapeutic agents. 53,54 Our findings indicate that the mechanism by which FANCI negatively regulates Akt is via recruitment of the PHLPP1 phosphatase to the PAF complex. Depletion of FANCI reduced the interaction between PHLPP1 and Akt and thereby induced a significant increase in Akt phosphorylation in a number of different human cell lines.…”

Section: Discussionmentioning

confidence: 76%

FANCI is a negative regulator of Akt activation

Zhang

Akhter

et al. 2016

Cell Cycle

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Akt is a critical mediator of the oncogenic PI3K pathway, and its activation is regulated by kinases and phosphatases acting in opposition. We report here the existence of a novel protein complex that is composed minimally of Akt, PHLPP1, PHLPP2, FANCI, FANCD2, USP1 and UAF1. Our studies show that depletion of FANCI, but not FANCD2 or USP1, results in increased phosphorylation and activation of Akt. This activation is due to a reduction in the interaction between PHLPP1 and Akt in the absence of FANCI. In response to DNA damage or growth factor treatment, the interactions between Akt, PHLPP1 and FANCI are reduced consistent with the known phosphorylation of Akt in response to these stimuli. Furthermore, depletion of FANCI results in reduced apoptosis after DNA damage in accord with its role as a negative regular of Akt. Our findings describe an unexpected function for FANCI in the regulation of Akt and define a previously unrecognized intersection between the PI3K-Akt and FA pathways.

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FANCD2 re-expression is associated with glioma grade and chemical inhibition of the Fanconi Anaemia pathway sensitises gliomas to chemotherapeutic agents

Cited by 34 publications

References 29 publications

Signaling pathways activation profiles make better markers of cancer than expression of individual genes

Signaling pathways activation profiles make better markers of cancer than expression of individual genes

Enhanced Histone Deacetylase Activity in Malignant Melanoma Provokes RAD51 and FANCD2-Triggered Drug Resistance

FANCI is a negative regulator of Akt activation

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