Genes & Cancer

HOXA10 is associated with temozolomide resistance through regulation of the homologous recombinant DNA repair pathway in glioblastoma cell lines

Jin Wook Kim MD1,*,Ji Young Kim MS1,*, Ja Eun Kim1, Seung-Ki Kim1,2, Hyun-Tai Chung1, and Chul-Kee Park1

1 Department of Neurosurgery, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea

2 Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children’s Hospital, Seoul, Korea;

* These authors contributed equally to this paper.

Correspondence:

Chul-Kee Park, email:

Keywords: HOXA10, temozolomide resistance, homologous recombination, EGR1, PTEN

Received: April 7, 2014 Accepted: June 25, 2014 Published: June 25, 2014

Abstract

Temozolomide resistance is associated with multiple DNA repair pathways. We investigated homeobox (HOX) genes for their role in temozolomide resistance, focusing on the homologous recombination (HR) pathway, and we tested their therapeutic implications in conjunction with O6-methylguanine DNA methyltransferase (MGMT) status. Two glioblastoma cell lines with different MGMT statuses were used to test the augmented anticancer effect of temozolomide with HOXA10 inhibition. In vitro experiments, including gene expression studies with RNA interference, were performed to verify the related pathway dynamics. HOXA10 inhibition reinforced temozolomide sensitivity independent of MGMT status and was related to the impaired double-strand DNA breakage repair process resulting from the downregulation of Rad51 paralogs. Early growth response 1 (EGR1) and phosphatase and tensin homolog (PTEN) were the regulatory mediators between HOXA10 and the HR pathway. Moreover, HOXA10 inhibition selectively affected the nuclear function of PTEN without interfering with its cytoplasmic function of suppressing the phosphoinositide 3-kinase/Akt pathway. The mechanism of HR pathway regulation by HOXA10 harbors another target mechanism for overcoming temozolomide resistance in glioblastoma patients.


PII: 16