Résumé
Abstract only Phosphatase and tensin homolog (PTEN) is a key tumor suppressor whose loss is commonly found in glioblastoma multiforme (GBM). In GBM, loss of PTEN leads to inactivation of signal transducer and activator of transcription 3 (STAT3). In contrast to the pro‐oncogenic function of STAT3 in other tumors, STAT3 has emerged as a key tumor suppressor in PTEN −/− GBM. We report for the first time a histone deacetylase 7 (HDAC7) mediated mechanism of STAT3 activation in PTEN −/− GBM. SiRNA induced depletion of HDAC7 in human U87 glioma cells triggered (both in vitro and in vivo ) phosphorylation of STAT3 on Y705. In accordance to our previous data, we show that this event is dependent of A‐kinase anchor protein 12 (AKAP12), which is rapidly induced upon HDAC7 silencing. In vivo , siRNA mediated HDAC7 repression abrogated tumor growth in U87‐glioma chick‐chorioallantoic membrane animal model. This effect was reversible when AKAP12 was co‐supressed. Intrigued by the macroscopical appearance of U87 tumors upon HDAC7 silencing, exhibiting small, pale nodules with prominent hemorrhage, we verified if defects in angiogenesis may explain the lack of tumor growth. Indeed, lectin‐based staining of the tumor vasculature revealed a significantly decreased vessel density. We demonstrate that several angiogenesis relevant genes (e.g. angiopoietin 1, angiogenin, interleukin 8) were significantly down‐regulated at transcriptional level. The present study highlights a STAT3 dependent pathway for suppressing the growth PTEN −/− GBM with potential for clinical translation. This work is sponsored by FNRS, Belgium.