Hedgehog signaling pathway and its targets for treatment in basal cell carcinoma

Basal cell carcinoma (BCC) of the skin is the most common type of cancer, and accounts for up to 40% of all cancers in the United States with a growing incidence rate in the last decades in all developed countries. Surgery is curative for most patients, although it leaves unaesthetic scars, but those that develop locally advanced or metastatic BCC require different therapeutical approaches. Furthermore, patients with BCC present an high risk of developing additional tumors. The increasing economic burden and the morbidity of BCC render of primary interest the development of targeted treatments for this disease. Among the molecular signals involved in the development of BCC, it has become evident the critical role of the morphogenic Hedgehog (Hh) pathway. This pathway is found altered and activated in almost all the BCC, both sporadic or inherited. Given the centrality of the Hh pathway in the pathophysiology of BCC, the primary efforts to identify molecular targets for the topical or systemic treatment of this cancer have focused on the Hedgehog components. Several Hh inhibitors have been so far identified, from the first, the natural cyclopamine to the recently FDA-approved synthetic Vismodegib, most targeting the Hh receptor Smo (either its function or its translocation to the primary cilium). Other molecules await further characterization (Bisamides compounds), while drugs currently approved for other diseases such as Itraconazole (a antimicotic agent) and Vitamin D3 have been tested on BCC with encouraging results. The outcome of the numerous ongoing clinical trials is expected to expand the field in short time. Further research is needed to obtain drugs targeting downstream components of the Hh pathway (eg Gli) or to exploit combinatorial therapies (eg with PI3K inhibitors, or retinoids) in order to overcome potential drug resistance

Identification and Characterization of KCASH2 and KCASH3, 2 Novel Cullin3 Adaptors Suppressing Histone Deacetylase and Hedgehog Activity in Medulloblastoma12

Medulloblastoma is the most common pediatric malignant brain tumor, arising from aberrant cerebellar precursors' development, a process mainly controlled by Hedgehog (Hh) signaling pathway. Histone deacetylase HDAC1 has been recently shown to modulate Hh signaling, deacetylating its effectors Gli1/2 and enhancing their transcriptional activity. Therefore, HDAC may represent a potential therapeutic target for Hh-dependent tumors, but still little information is available on the physiological mechanisms of HDAC regulation. The putative tumor suppressor RENKCTD11 acts through ubiquitination-dependent degradation of HDAC1, thereby affecting Hh activity and medulloblastoma growth. We identify and characterize here two RENKCTD11 homologues, defining a new family of proteins named KCASH, as “KCTD containing, Cullin3 adaptor, suppressor of Hedgehog.” Indeed, the novel genes (KCASH2KCTD21 and KCASH3KCTD6) share with RENKCTD11 a number of features, such as a BTB domain required for the formation of a Cullin3 ubiquitin ligase complex and HDAC1 ubiquitination and degradation capability, suppressing the acetylation-dependent Hh/Gli signaling. Expression of KCASH2 and -3 is observed in cerebellum, whereas epigenetic silencing and allelic deletion are observed in human medulloblastoma. Rescuing KCASHs expression reduces the Hedgehog-dependent medulloblastoma growth, suggesting that loss of members of this novel family of native HDAC inhibitors is crucial in sustaining Hh pathway-mediated tumorigenesis. Accordingly, they might represent a promising class of endogenous “agents” through which this pathway may be targeted