Abstract
APE1 is essential in cancer cells due to its central role in the Base Excision Repair pathway of DNA lesions and in the transcriptional regulation of genes involved in tumor progression/chemoresistance. Indeed, APE1 overexpression correlates with chemoresistance in more aggressive cancers, and APE1 protein-protein interactions (PPIs) specifically modulate different protein functions in cancer cells. Although important, a detailed investigation on the nature and function of protein interactors regulating APE1 role in tumor progression and chemoresistance is still lacking. The present work was aimed at analyzing the APE1-PPI network with the goal of defining bad prognosis signatures through systematic bioinformatics analysis. By using a well-characterized HeLa cell model stably expressing a flagged APE1 form, which was subjected to extensive proteomics analyses for immunocaptured complexes from different subcellular compartments, we here demonstrate that APE1 is a central hub connecting different subnetworks largely composed of proteins belonging to cancer-associated communities and/or involved in RNA- and DNA-metabolism. When we performed survival analysis in real cancer datasets, we observed that more than 80% of these APE1-PPI network elements is associated with bad prognosis. Our findings, which are hypothesis generating, strongly support the possibility to infer APE1-interactomic signatures associated with bad prognosis of different cancers; they will be of general interest for the future definition of novel predictive disease biomarkers. Future studies will be needed to assess the function of APE1 in the protein complexes we discovered. Data are available via ProteomeXchange with identifier PXD013368.
Highlights
Alteration of DNA repair mechanisms is an important hallmark of cancer cells, and plays a role both in the onset of an initial cancerous phenotype and in tumor progression
After careful filtration for false positives identified in the corresponding control (SCR and res) samples, 62, 31 and 394 proteins were identified as potential APE1 interactors in the wholecell lysate, nuclear fraction and cytoplasmic fractions, respectively, which accounted for 455 non-redundant proteins
The above-mentioned protein inventory was subjected to bioinformatics analysis to establish a protein-protein interactions (PPIs)-network associated with APE1 (Fig. 1); we linked this analysis to additional cancer/biological databases with the aim to provide a more complete picture of the APE1 biological roles in both cancer and cellular biology
Summary
Alteration of DNA repair mechanisms is an important hallmark of cancer cells, and plays a role both in the onset of an initial cancerous phenotype and in tumor progression. The efficacy of novel APE1/NPM1 interaction inhibitors, which sensitize cancer cells to chemotherapy agents, supports the translational importance of these findings[26] These results further support the hypothesis that an alteration of other APE1 PPIs may be causally involved in cancer development and chemoresistance. Prompted by these observations, the present work was aimed at: i) implementing the already known APE1-PPI network using a more efficient functional proteomics approach, and ii) defining the association of the APE1-PPI network with the modulation of tumor progression and chemoresistance through a systematic bioinformatics analysis of the Cancer Genome Atlas (TCGA) datasets. Our findings support the possibility to infer APE1 interactomic signatures associated with bad prognosis of different cancers and will be of general interest for the definition of novel predictive biomarker signatures of cancers
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