Role of promoter hypermethylation in Cisplatin treatment response of male germ cell tumors View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2004-12

AUTHORS

Sanjay Koul, James M McKiernan, Gopeshwar Narayan, Jane Houldsworth, Jennifer Bacik, Deborah L Dobrzynski, Adel M Assaad, Mahesh Mansukhani, Victor E Reuter, George J Bosl, Raju SK Chaganti, Vundavalli VVS Murty

ABSTRACT

BACKGROUND: Male germ cell tumor (GCT) is a highly curable malignancy, which exhibits exquisite sensitivity to cisplatin treatment. The genetic pathway(s) that determine the chemotherapy sensitivity in GCT remain largely unknown. RESULTS: We studied epigenetic changes in relation to cisplatin response by examining promoter hypermethylation in a cohort of resistant and sensitive GCTs. Here, we show that promoter hypermethylation of RASSF1A and HIC1 genes is associated with resistance. The promoter hypermethylation and/or the down-regulated expression of MGMT is seen in the majority of tumors. We hypothesize that these epigenetic alterations affecting MGMT play a major role in the exquisite sensitivity to cisplatin, characteristic of GCTs. We also demonstrate that cisplatin treatment induce de novo promoter hypermethylation in vivo. In addition, we show that the acquired cisplatin resistance in vitro alters the expression of specific genes and the highly resistant cells fail to reactivate gene expression after treatment to demethylating and histone deacetylase inhibiting agents. CONCLUSIONS: Our findings suggest that promoter hypermethylation of RASSF1A and HIC1 genes play a role in resistance of GCT, while the transcriptional inactivation of MGMT by epigenetic alterations confer exquisite sensitivity to cisplatin. These results also implicate defects in epigenetic pathways that regulate gene transcription in cisplatin resistant GCT. More... »

PAGES

16

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/1476-4598-3-16

DOI

http://dx.doi.org/10.1186/1476-4598-3-16

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1016725799

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/15149548


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