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 chemotherapy approaches. The effort the scientific community is lavishing on the never-ending battle against GBM is reflected by the huge number of clinical trials launched, about 2003 on 10 September 2024. However, we are still far from both an in-depth comprehension of the biological and molecular processes leading to GBM onset and progression and, importantly, a cure. GBM is provided with high intratumoral heterogeneity, immunosuppressive capacity, and infiltrative ability due to neoangiogenesis. These features impact both tumour aggressiveness and therapeutic vulnerability, which is further limited by the presence in the tumour core of niches of glioblastoma stem cells (GSCs) that are 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 the 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, and 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 of proposing its inhibition as a valuable therapeutic route for this deadly brain tumour.