Histone Deacetylase 6 Represents a Novel Drug Target in the Oncogenic Hedgehog Signaling Pathway

Abstract

Uncontrolled Hedgehog (Hh) signaling is the cause of several malignancies, including the pediatric cancer medulloblastoma, a neuroectodermal tumor affecting the cerebellum. Despite the development of potent Hh pathway antagonists, medulloblastoma drug resistance is still an unresolved issue that requires the identification of novel drug targets. Following up on our observation that histone deacetylase 6 (HDAC6) expression was increased in Hh-driven medulloblastoma, we found that this enzyme is essential for full Hh pathway activation. Intriguingly, these stimulatory effects of HDAC6 are partly integrated downstream of primary cilia, a known HDAC6-regulated structure. In addition, HDAC6 is also required for the complete repression of basal Hh target gene expression. These contrasting effects are mediated by HDAC6 0 s impact on Gli2 mRNA and GLI3 protein expression. As a result of this complex interaction with Hh signaling, global transcriptome analysis revealed that HDAC6 regulates only a subset of Smoothened-and Gli-driven genes, including all well-established Hh targets such as Ptch1 or Gli1. Importantly, medulloblastoma cell survival was severely compromised by HDAC6 inhibition in vitro and pharmacologic HDAC6 blockade strongly reduced tumor growth in an in vivo allograft model. In summary, our data describe an important role for HDAC6 in regulating the mammalian Hh pathway and encourage further studies focusing on HDAC6 as a novel drug target in medulloblastoma.

Selective targeting of HDAC1/2 elicits anticancer effects through Gli1 acetylation in preclinical models of SHH Medulloblastoma

“…In a previous report it was observed that, in addition to HDAC1/2, HDAC6 is also upregulated in SHH-MB and its targeting leads to a substantial anti-tumor effect in mouse models of SHH-MB29. Interestingly, HDAC6 seems to exert its function independently of Gli acetylation, by acting at both receptor and downstream level, most likely by affecting Gli2/3 stability.…”

“…Indeed, HDAC1/2 deacetylate and enhance Gli1 transcriptional activity, thus suggesting that, by blocking these enzymes, MGCD0103 may inhibit Hh function via Gli1 acetylation. Since in a recent work it was also observed that HDAC6 inhibits Hh signaling by acting both upstream and downstream of Sufu29, we first tested at what level the inhibitory effect of MGCD0103 occurs. To this end, we used the Sufu −/− MEF cells, where the absence of the cytoplasmic inhibitor Sufu causes an increase of Hh target gene expression, independently of the receptor (Ptch1/Smo) activation30.…”

Targeting GLI factors to inhibit the Hedgehog pathway

“…These findings suggest that selective inhibition of HDAC6 can represents a new therapeutic approach in the treatment of Hh-dependent malignancies. Indeed, the specific HDAC6 antagonist, ACY-1215 [70] ( Figures 1 and 2 and Table 1), reduced strikingly in vivo tumor growth. Hence, HDAC6, despite exerting a dichotomous role (it is required to achieve full pathway activity, but it has also been described to repress basal Hh target gene transcription) is a critical player in Hh pathway regulation, promoting the maximum expression of a subset of GLI target genes [70].…”

“…Indeed, the specific HDAC6 antagonist, ACY-1215 [70] ( Figures 1 and 2 and Table 1), reduced strikingly in vivo tumor growth. Hence, HDAC6, despite exerting a dichotomous role (it is required to achieve full pathway activity, but it has also been described to repress basal Hh target gene transcription) is a critical player in Hh pathway regulation, promoting the maximum expression of a subset of GLI target genes [70]. Since the upregulation of HDACs has been documented in various types of tumors, the development of novel potent and selective HDACi is ongoing.…”

A genome scale RNAi screen identifies GLI1 as a novel gene regulating vorinostat sensitivity

“…A similar induction of GLI1 was observed in MEFs treated with the pan-HDACi trichostatin A. 34 The canonical role of GLI1 is as a key transcription factor and effector molecule in the Hedgehog signaling pathway. 25 As SMO inhibition did not sensitize to vorinostat-induced apoptosis, GLI1 appears to function through a noncanonical pathway in this system.…”