Reversing HOXA9 oncogene activation by PI3K inhibition: epigenetic mechanism and prognostic significance in human glioblastoma.
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.
Costa
Bruno M
BM
The Brain Tumor Research Center, Department of Neurological Surgery, University of California-San Francisco, San Francisco, California 94158-9001, USA.
Smith
Justin S
JS
Chen
Ying
Y
Chen
Justin
J
Phillips
Heidi S
HS
Aldape
Kenneth D
KD
Zardo
Giuseppe
G
Nigro
Janice
J
James
C David
CD
Fridlyand
Jane
J
Reis
Rui M
RM
Costello
Joseph F
JF
D000328:Adult; D017209:Apoptosis / Q000235:genetics; D001254:Astrocytoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000235:genetics; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D018572:Disease-Free Survival; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006657:Histones / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011401:Promoter Regions, Genetic; D015996:Survival Rate; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000235:genetics
D015254:DNA Modification Methylases; D045643:DNA Repair Enzymes; D006657:Histones; D018398:Homeodomain Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D025521:Tumor Suppressor Proteins; C097899:homeobox protein HOXA9; C515491:MGMT protein, human