KCTD1 is a new modulator of the KCASH family of Hedgehog suppressors.

The Sonic Hedgehog (Hh) signal transduction pathway plays a critical role in many developmental processes and, when deregulated, may contribute to several cancers, including basal cell carcinoma, medulloblastoma, colorectal, prostate, and pancreatic cancer. In recent years, several Hh inhibitors have been developed, mainly acting on the Smo receptor. However, drug resistance due to Smo mutations or non-canonical Hh pathway activation highlights the need to identify further mechanisms of Hh pathway modulation. Among these, deacetylation of the Hh transcription factor Gli1 by the histone deacetylase HDAC1 increases Hh activity. On the other end, the KCASH family of oncosuppressors binds HDAC1, leading to its ubiquitination and subsequent proteasomal degradation, leaving Gli1 acetylated and not active. It was recently demonstrated that the potassium channel containing protein KCTD15 is able to interact with KCASH2 protein and stabilize it, enhancing its effect on HDAC1 and Hh pathway. KCTD15 and KCTD1 proteins share a high homology and are clustered in a specific KCTD subfamily. We characterize here KCTD1 role on the Hh pathway. Therefore, we demonstrated KCTD1 interaction with KCASH1 and KCASH2 proteins, and its role in their stabilization by reducing their ubiquitination and proteasome-mediated degradation. Consequently, KCTD1 expression reduces HDAC1 protein levels and Hh/Gli1 activity, inhibiting Hh dependent cell proliferation in Hh tumour cells. Furthermore, analysis of expression data on publicly available databases indicates that KCTD1 expression is reduced in Hh dependent MB samples, compared to normal cerebella, suggesting that KCTD1 may represent a new putative target for therapeutic approaches against Hh-dependent tumour.

"Radiotherapy for thymic epithelial tumors: What is the optimal dose? A systematic review."

Thymic epithelial tumors (TETs) are rare thoracic tumors, often requiring multimodal approaches. Surgery represents the first step of the treatment, possibly followed by adjuvant radiotherapy (RT) and, less frequently, chemotherapy. For unresectable tumors, a combination of chemotherapy and RT is often used. Currently, the optimal dose for patients undergoing radiation is not clearly defined. Current guidelines on RT are based on studies with a low level of evidence, where 2D RT was widely used. We aim to shed light on the optimal radiation dose for patients with TETs undergoing RT through a systematic review of the recent literature, including reports using modern RT techniques such as 3D-CRT, IMRT/VMAT, or proton-therapy. A comprehensive literature search of four databases was conducted following the PRISMA guidelines. Two investigators independently screened and reviewed the retrieved references. Reports with < 20 patients, 2D-RT use only, median follow-up time < 5 years, and reviews were excluded. Two studies fulfilled all the criteria and therefore were included. Loosening the follow-up time criteria to > 3 years, three additional studies could be evaluated. A total of 193 patients were analyzed, stratified for prognostic factors (histology, stage, and completeness of resection), and synthesized according to the synthesis without meta-analysis (SWIM) method. The paucity and heterogeneity of eligible studies led to controversial results. The optimal RT dose neither for postoperative, nor primary RT in the era of modern RT univocally emerged. Conversely, this overview can spark new evidence to define the optimal RT dose for each TETs category.