An integrated epigenome and transcriptome analysis identifies PAX2 as a master regulator of drug resistance in high grade pancreatic ductal adenocarcinoma

Autoři: Imlimaong Aier aff001;  Rahul Semwal aff002;  Aiindrila Dhara aff003;  Nirmalya Sen aff003;  Pritish Kumar Varadwaj aff001
Působiště autorů: Department of Bioinformatics & Applied Sciences, Indian Institute of Information Technology—Allahabad, Uttar Pradesh, India aff001;  Department of Information Technology, Indian Institute of Information Technology—Allahabad, Uttar Pradesh, India aff002;  Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Trivandrum, Kerala, India aff003;  S.N.Bose Innovation Centre, University Of Kalyani, Nadia, West Bengal, India aff004
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0223554


Pancreatic ductal adenocarcinoma (PDAC) is notoriously difficult to treat due to its aggressive, ever resilient nature. A major drawback lies in its tumor grade; a phenomenon observed across various carcinomas, where highly differentiated and undifferentiated tumor grades, termed as low and high grade respectively, are found in the same tumor. One eminent problem due to such heterogeneity is drug resistance in PDAC. This has been implicated to ABC transporter family of proteins that are upregulated in PDAC patients. However, the regulation of these transporters with respect to tumor grade in PDAC is not well understood. To combat these issues, a study was designed to identify novel genes that might regulate drug resistance phenotype and be used as targets. By integrating epigenome with transcriptome data, several genes were identified based around high grade PDAC. Further analysis indicated oncogenic PAX2 transcription factor as a novel regulator of drug resistance in high grade PDAC cell lines. It was observed that silencing of PAX2 resulted in increased susceptibility of high grade PDAC cells to various chemotherapeutic drugs. Mechanistically, the study showed that PAX2 protein can bind and alter transcriptionally; expression of many ABC transporter genes in high grade PDAC cell lines. Overall, the study indicated that PAX2 significantly upregulated ABC family of genes resulting in drug resistance and poor survival in PDAC.

Klíčová slova:

Drug regulation – Gene expression – Gene ontologies – Gene regulation – Genetic networks – Pancreatic cancer – Small interfering RNAs – Transcriptional control


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