Journal
CANCER RESEARCH
Volume 70, Issue 2, Pages 453-462Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-09-2189
Keywords
-
Categories
Funding
- NIH [NIH CA094971]
- NIH/NCI [F32 CA113039-01]
- Karen Osney Brownstein Endowed Chair
- UC [Bio05-10501]
- Portuguese Science and Technology Foundation [SFRH/BD/15258/2004]
- Luso-American Development Foundation, Portugal [186/06]
- Fundação para a Ciência e a Tecnologia [SFRH/BD/15258/2004] Funding Source: FCT
Ask authors/readers for more resources
HOXA genes encode critical transcriptional regulators of embryonic development that have been implicated in cancer. In this study, we documented functional relevance and mechanism of activation of HOXA9 in glioblastoma (GBM), the most common malignant brain tumor. Expression of HOXA genes was investigated using reverse transcription-PCR in primary gliomas and glioblastoma cell lines and was validated in two sets of expression array data. In a subset of GBM, HOXA genes are aberrently activated within confined chromosomal domains. Transcriptional activation of the HOXA cluster was reversible by a phosphoinostide 3-kinase (PI3K) inhibitor through an epigenetic mechanism involving histone H3K27 trimethylation. Functional studies of HOXA9 showed its capacity to decrease apoptosis and increase cellular proliferation along with tumor necrosis factor-related apoptosis-including ligand resistance. Notably, aberrant expression of HOXA9 was independently predictive of shorter overall and progression-free survival in two GBM patient sets and improved survival prediction by MGMT promoter methylation. Thus, HOXA9 activation is a novel, independent, and negative prognostic marker in GBM that is reversible through a PI3K-associated epigenetic mechanism. Our findings suggest a transcriptional pathway through which PI3K activates oncogenic HOXA expression with implications for mTOR or PI3K targeted therapies. Cancer Res; 70(2); 453-62. (C)2010 AACR.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available