The cylindromatosis (CYLD) gene and head and neck tumorigenesis

Abstract

Germline CYLD mutation is associated with the development of a rare inheritable syndrome, called the CYLD cutaneous syndrome. Patients with this syndrome are distinctly presented with multiple tumors in the head and neck region, which can grow in size and number over time. Some of these benign head and neck tumors can turn into malignancies in some individuals. CYLD has been identified to be the only tumor suppressor gene reported to be associated with this syndrome thus far. Here, we summarize all reported CYLD germline mutations associated with this syndrome, as well as the reported paired somatic CYLD mutations of the developed tumors. Interestingly, whole-exome sequencing (WES) studies of multiple cancer types also revealed CYLD mutations in many human malignancies, including head and neck cancers and several epithelial cancers. Currently, the role of CYLD mutations in head and neck carcinogenesis and other cancers is poorly defined. We hope that this timely review of recent findings on CYLD genetics and animal models for oncogenesis can provide important insights into the mechanism of head and neck tumorigenesis.

Keywords: Brooke-Spiegler Syndrome (BSS); Cylindromatosis (CYLD); Deubiquitinating (DUB); Familial Cylindromatosis (FC); Head and Neck Cancer; Multiple Familial Trichoepithelioma (MFT1); Nuclear Factor-kB (NF-kB); TNF-receptor associated factor (TRAF) proteins; The CYLD cutaneous syndrome; Turban Tumor Syndrome; and B-cell lymphoma 3 (Bcl-3); tumorigenesis.

Fig. 1

Reported CYLD germline mutations in patients with the CYLD cutaneous syndrome [, , , –23, 25, 26, 81, 120]. The frequency of familial cases of CYLD cutaneous syndrome with germline CYLD mutations, and the corresponding amino acid positions affected by these mutations are indicated (as detailed in Table 1 and predicted using the Integrative Genomics Viewer (IGV) software, the Broad Institute, USA). The CYLD protein contains three CAP-GLY domains (aa 155–198, 253–286, 492–535), a UCH catalytic domain (aa 591–950) and a Zinc binding region (aa 778–842) within in the catalytic domain based on the NCBI number NP_056062.1

Fig. 2

CYLD-associated signaling pathways. NF-kB, Wnt/β-catenin, and JNK pathways have been shown to be regulated by CYLD. The canonical NF-kB signaling pathway has been shown to be regulated by CYLD through deubiquitination of target substrates such as RIP1, the TAK1 complex and NEMO [2]. In the non-canonical NF-kB signaling pathway, deubiquitination of Bcl-3 by CYLD results in the inhibition of cyclin D1 gene expression [29]. Wnt/β-catenin signaling has been shown to be regulated by CYLD, via deubiquitination of the (disheveled) DVL protein [6]. The JNK signaling pathway has been demonstrated to be regulated by CYLD activity through unknown mechanisms likely involving TRAF2 and MKK7 [7]. In addition, the Notch/Hes1 pathway and the Hedgehog signaling have been shown to regulate transcription of CYLD, via suppression of CYLD transcription by Hes1 and snail1, respectively [69, 70]. Blue arrows indicate nuclear translocation of the proteins. The lower grey box shows the published signaling changes and likely consequences of CYLD deficiencies due to CYLD knockout, CYLD silencing by siRNA or shRNA or CYLD mutation. Red arrows indicate that the nuclear translocation of the indicated proteins was found to be increased. Potential therapeutic targets due to CYLD aberrations are highlighted in red within the lower grey box