The Role of HDAC6 in Glioblastoma Multiforme: A New Avenue to Therapeutic Interventions?

Despite the great advances in basic research results, glioblastoma multiforme (GBM) still remains an incurable tumour. To date, a GBM diagnosis is a death sentence within 15-18 months, due to the high recurrence rate and resistance to conventional radio- and chemotheraphy approaches. The effort the scientific community is lavishing in the never-ending battle against GBM is reflected by the huge number of clinical trials enlisted in the clinicaltrials.gov website: about 2003 on september 10th 2024. However, we are still far both from an in-depth comprehension of the biological and molecular processes leading to GBM onset and progression and, importantly, from a cure. GBM is provided with a high intratumoral heterogeneity, immunosuppressive capacity and infiltrative ability due to neoangiogenesis. These features impact on both tumour aggressiveness and therapeutic vulnerability, which is further limited by the presence in the tumour core of niches of glioblastoma stem cells (GSCs), responsible for the relapse of this brain neoplasm. Epigenetic alterations may both drive and develop along GBM progression and also rely on changes in the expression of genes encoding histone modifying enzymes, including histone deacetylases (HDACs). Among them, HDAC6 – a cytoplasmic HDAC - has recently gained attention because of its role in modulating several biological aspects of GBM, including DNA repair ability, massive growth, radio-and chemoresistance, de-differentiation through primary cilia disruption. In this review article, the available information related to HDAC6 function in GBM will be presented, with the aim to propose its inhibition as a valuable therapeutic route for this deadly brain tumour.