HES6 gene is a strong glioma biomarker and a key transcriptional regulator needed for cancer cell growth

Malignant glioma is the most common brain tumor with 16,000 individuals diagnosed annually in the United States. We performed a systematic large-scale transcriptomics data mining study of 9,783 Affymetrix samples from the GeneSapiens database (www.genesapiens.org) to systematically identify genes that are most glioma-specific. We searched for genes that were highly expressed in 322 glioblastoma multiforme tissue samples and 66 anaplastic astrocytomas as compared to 425 samples from histologically normal central nervous system. Transcription cofactor HES6 (Hairy and Enhancer of Split 6) emerged as one of the most glioma-specific genes. Immunostaining of a tissue microarray showed HES6 expression in 335 (98.8%) out of the 339 glioma samples. HES6 was also expressed in endothelial cells in normal and glioma tissues. Recurrent grade 2 astrocytomas and grade 2-3 oligodendrogliomas showed higher levels of HES6 immunoreactivity than the corresponding primary tumors. Functional studies implied a critical role for HES6 in supporting survival of glioma cells, as evidenced by reduction of cancer cell proliferation and induction of Caspase 3/7 activity after HES6 silencing in A172 and LN405 cells. The biological role and consequences of HES6 silencing and overexpression was explored with genome-wide analyses, which implicated a role for HES6 in p53, c-myc, and NF-?B transcriptional networks. We conclude that HES6 has a critical role in sustaining glioma cell growth, survival, migration and possibly angiogenesis. HES6 is a potential therapeutic target and biomarker for glioma. This work was supported by funding under the 6th FP of the European Union, Project RIGHT (LSHB-CT-2004-005276), and the Academy of Finland.