{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T03:52:08Z","timestamp":1772164328962,"version":"3.50.1"},"reference-count":52,"publisher":"American Association for Cancer Research (AACR)","issue":"2","content-domain":{"domain":["aacrjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2010,1,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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\u2013PCR 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\u2013related 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\u201362<\/jats:p>","DOI":"10.1158\/0008-5472.can-09-2189","type":"journal-article","created":{"date-parts":[[2010,1,12]],"date-time":"2010-01-12T23:40:38Z","timestamp":1263339638000},"page":"453-462","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":126,"title":["Reversing\n                    <i>HOXA9<\/i>\n                    Oncogene Activation by PI3K Inhibition: Epigenetic Mechanism and Prognostic Significance in Human Glioblastoma"],"prefix":"10.1158","volume":"70","author":[{"given":"Bruno M.","family":"Costa","sequence":"first","affiliation":[{"name":"Authors' Affiliations:\u20081The Brain Tumor Research Center, Department of Neurological Surgery, University of California-San Francisco, San Francisco, California; 2Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; 3Department of Tumor Biology and Angiogenesis, Genentech, Inc., South San Francisco, California; 4Department of Pathology, M.D. Anderson Cancer Center, Houston, Texas; 5Department of Cellular Biotechnologies and Hematology, University of Rome-La Sapienza, Rome, Italy; and 6University of Bergen-Institute of Biomedicine, Bergen, Norway"},{"name":"Authors' Affiliations:\u20081The Brain Tumor Research Center, Department of Neurological Surgery, University of California-San Francisco, San Francisco, California; 2Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; 3Department of Tumor Biology and Angiogenesis, Genentech, Inc., South San Francisco, California; 4Department of Pathology, M.D. Anderson Cancer Center, Houston, Texas; 5Department of Cellular Biotechnologies and Hematology, University of Rome-La Sapienza, Rome, Italy; and 6University of Bergen-Institute of Biomedicine, Bergen, Norway"}]},{"given":"Justin S.","family":"Smith","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081The Brain Tumor Research Center, Department of Neurological Surgery, University of California-San Francisco, San Francisco, California; 2Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; 3Department of Tumor Biology and Angiogenesis, Genentech, Inc., South San Francisco, California; 4Department of Pathology, M.D. Anderson Cancer Center, Houston, Texas; 5Department of Cellular Biotechnologies and Hematology, University of Rome-La Sapienza, Rome, Italy; and 6University of Bergen-Institute of Biomedicine, Bergen, Norway"}]},{"given":"Ying","family":"Chen","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081The Brain Tumor Research Center, Department of Neurological Surgery, University of California-San Francisco, San Francisco, California; 2Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; 3Department of Tumor Biology and Angiogenesis, Genentech, Inc., South San Francisco, California; 4Department of Pathology, M.D. Anderson Cancer Center, Houston, Texas; 5Department of Cellular Biotechnologies and Hematology, University of Rome-La Sapienza, Rome, Italy; and 6University of Bergen-Institute of Biomedicine, Bergen, Norway"}]},{"given":"Justin","family":"Chen","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081The Brain Tumor Research Center, Department of Neurological Surgery, University of California-San Francisco, San Francisco, California; 2Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; 3Department of Tumor Biology and Angiogenesis, Genentech, Inc., South San Francisco, California; 4Department of Pathology, M.D. Anderson Cancer Center, Houston, Texas; 5Department of Cellular Biotechnologies and Hematology, University of Rome-La Sapienza, Rome, Italy; and 6University of Bergen-Institute of Biomedicine, Bergen, Norway"}]},{"given":"Heidi S.","family":"Phillips","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081The Brain Tumor Research Center, Department of Neurological Surgery, University of California-San Francisco, San Francisco, California; 2Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; 3Department of Tumor Biology and Angiogenesis, Genentech, Inc., South San Francisco, California; 4Department of Pathology, M.D. Anderson Cancer Center, Houston, Texas; 5Department of Cellular Biotechnologies and Hematology, University of Rome-La Sapienza, Rome, Italy; and 6University of Bergen-Institute of Biomedicine, Bergen, Norway"}]},{"given":"Kenneth D.","family":"Aldape","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081The Brain Tumor Research Center, Department of Neurological Surgery, University of California-San Francisco, San Francisco, California; 2Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; 3Department of Tumor Biology and Angiogenesis, Genentech, Inc., South San Francisco, California; 4Department of Pathology, M.D. Anderson Cancer Center, Houston, Texas; 5Department of Cellular Biotechnologies and Hematology, University of Rome-La Sapienza, Rome, Italy; and 6University of Bergen-Institute of Biomedicine, Bergen, Norway"}]},{"given":"Giuseppe","family":"Zardo","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081The Brain Tumor Research Center, Department of Neurological Surgery, University of California-San Francisco, San Francisco, California; 2Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; 3Department of Tumor Biology and Angiogenesis, Genentech, Inc., South San Francisco, California; 4Department of Pathology, M.D. Anderson Cancer Center, Houston, Texas; 5Department of Cellular Biotechnologies and Hematology, University of Rome-La Sapienza, Rome, Italy; and 6University of Bergen-Institute of Biomedicine, Bergen, Norway"},{"name":"Authors' Affiliations:\u20081The Brain Tumor Research Center, Department of Neurological Surgery, University of California-San Francisco, San Francisco, California; 2Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; 3Department of Tumor Biology and Angiogenesis, Genentech, Inc., South San Francisco, California; 4Department of Pathology, M.D. Anderson Cancer Center, Houston, Texas; 5Department of Cellular Biotechnologies and Hematology, University of Rome-La Sapienza, Rome, Italy; and 6University of Bergen-Institute of Biomedicine, Bergen, Norway"}]},{"given":"Janice","family":"Nigro","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081The Brain Tumor Research Center, Department of Neurological Surgery, University of California-San Francisco, San Francisco, California; 2Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; 3Department of Tumor Biology and Angiogenesis, Genentech, Inc., South San Francisco, California; 4Department of Pathology, M.D. Anderson Cancer Center, Houston, Texas; 5Department of Cellular Biotechnologies and Hematology, University of Rome-La Sapienza, Rome, Italy; and 6University of Bergen-Institute of Biomedicine, Bergen, Norway"}]},{"given":"C. David","family":"James","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081The Brain Tumor Research Center, Department of Neurological Surgery, University of California-San Francisco, San Francisco, California; 2Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; 3Department of Tumor Biology and Angiogenesis, Genentech, Inc., South San Francisco, California; 4Department of Pathology, M.D. Anderson Cancer Center, Houston, Texas; 5Department of Cellular Biotechnologies and Hematology, University of Rome-La Sapienza, Rome, Italy; and 6University of Bergen-Institute of Biomedicine, Bergen, Norway"}]},{"given":"Jane","family":"Fridlyand","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081The Brain Tumor Research Center, Department of Neurological Surgery, University of California-San Francisco, San Francisco, California; 2Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; 3Department of Tumor Biology and Angiogenesis, Genentech, Inc., South San Francisco, California; 4Department of Pathology, M.D. Anderson Cancer Center, Houston, Texas; 5Department of Cellular Biotechnologies and Hematology, University of Rome-La Sapienza, Rome, Italy; and 6University of Bergen-Institute of Biomedicine, Bergen, Norway"}]},{"given":"Rui M.","family":"Reis","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081The Brain Tumor Research Center, Department of Neurological Surgery, University of California-San Francisco, San Francisco, California; 2Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; 3Department of Tumor Biology and Angiogenesis, Genentech, Inc., South San Francisco, California; 4Department of Pathology, M.D. Anderson Cancer Center, Houston, Texas; 5Department of Cellular Biotechnologies and Hematology, University of Rome-La Sapienza, Rome, Italy; and 6University of Bergen-Institute of Biomedicine, Bergen, Norway"}]},{"given":"Joseph F.","family":"Costello","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081The Brain Tumor Research Center, Department of Neurological Surgery, University of California-San Francisco, San Francisco, California; 2Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; 3Department of Tumor Biology and Angiogenesis, Genentech, Inc., South San Francisco, California; 4Department of Pathology, M.D. Anderson Cancer Center, Houston, Texas; 5Department of Cellular Biotechnologies and Hematology, University of Rome-La Sapienza, Rome, Italy; and 6University of Bergen-Institute of Biomedicine, Bergen, 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