Hedgehog and HDAC6 in cancers: dissection of dysregulated biological mechanisms and potential therapeutic treatments

The Hedgehog (Hh) signaling pathway serves as a pivotal regulator of cell differentiation, and its abnormal activation is a driving force behind tumorigenesis. While inhibitors targeting the Hh pathway have been developed, a significant portion of tumors with heightened Hh expression exhibit resistance to chemotherapy and tend to relapse. This pathway transmits its signals through the primary cilium, a structure typically found in non-proliferating mammalian cells. Cancer cells often lack cilia, thus the restoration of these structures is emerging as a promising therapeutic approach. Among the compounds targeting the primary cilium is the inhibitor of histone deacetylase HDAC6. Both Hh signaling and HDAC6 are associated with the primary cilium. We hypothesized that a combination therapy targeting Hh, HDAC6, and cilium could synergistically combat chemo-resistance in tumors overexpressing Hh/HDAC6. To validate our hypothesis, we dissected the Hh/HDAC6-dependent biological mechanisms relevant to tumor resistance and relapse. We demonstrated the efficacy of a combination therapy in treating acute myeloid leukemia and glioblastoma multiforme both in vitro and in zebrafish. Furthermore, we are exploring the potential of inhibiting other HDAC isoforms, such as HDAC8, as anticancer agents, with the ultimate aim of enhancing treatment specificity and reducing the duration and dosage of exposure.