Tumor Suppressor Function of CYLD in Nonmelanoma Skin Cancer

Abstract

Ubiquitin and ubiquitin-related proteins posttranslationally modify substrates, and thereby alter the functions of their targets. The ubiquitination process is involved in various physiological responses, and dysregulation of components of the ubiquitin system has been linked to many diseases including skin cancer. The ubiquitin pathways activated among skin cancers are highly diverse and may reflect the various characteristics of the cancer type. Basal cell carcinoma and squamous cell carcinoma, the most common types of human skin cancer, are instances where the involvement of the deubiquitination enzyme CYLD has been recently highlighted. In basal cell carcinoma, the tumor suppressor protein CYLD is repressed at the transcriptional levels through hedgehog signaling pathway. Downregulation of CYLD in basal cell carcinoma was also shown to interfere with TrkC expression and signaling, thereby promoting cancer progression. By contrast, the level of CYLD is unchanged in squamous cell carcinoma, instead, catalytic inactivation of CYLD in the skin has been linked to the development of squamous cell carcinoma. This paper will focus on the current knowledge that links CYLD to nonmelanoma skin cancers and will explore recent insights regarding CYLD regulation of NF-κB and hedgehog signaling during the development and progression of these types of human tumors.

Large Germline Deletions of the CYLD Gene in Patients With Brooke–Spiegler Syndrome and Multiple Familial Trichoepithelioma

“…CYLD plays a key role, as an inhibitor protein, in the NF-kB, JNK, and Wnt signaling pathways. 3,26,[30][31][32][33][34][35] Various germline mutations in CYLD have been found in BSS/MFT, mostly involving the coding sequence and exon-intron junction sites, especially in the regions where conserved enzymatic domains are encoded. 3,[36][37][38][39][40] Rarely, a germline CYLD mutation in a deep intronic region 41 or a large germline CYLD deletion have been reported.…”

miR‑454 promotes survival and induces oxaliplatin resistance in gastric carcinoma cells by targeting CYLD

“…The overexpression of miR454 in gastric cancer tissues has been previously reported (23) where it was hypothesized that overexpression of miR-454 was associated with the advancement of the clinical stage, metastases of the lymph node and a poor prognosis for patients. CYLD acts as a suppressor in many types of tumor including breast cancer and non-melanoma skin cancer (24,25). Both miR-425-5p and miR-20a promote the progression of gastric cancer via regulating CYLD (26,27).…”

A case report of a female patient with Brooke-Spiegler syndrome

“…Novija saznanja ukazuju na to da ovi sindromi, koji predstavljaju rezultat defekta u putativnoj stem ćelijskoj regulaciji folikulo-sebacealne apokrine jedinice, što omogućava razvoj različitih tumora kože (11,12), ne dele samo zajedničku genetsku osnovu, već predstavljaju i fenotipske varijacije iste bolesti (13). Gen CYLD ima tumorsupresivnu funkciju u razvoju različitih karcinoma, kao što su karcinom kolona, pluća, melanom, multipli mijelom i drugi (8), tako da osoba sa mutiranim supresornim CYLD genom ima visok rizik od razvoja ovih tumora (14).…”

“…Treba napomenuti da kod BRSS postoji mogućnost nastanka maligne alteracije s razvojem metastaza (8). Bolesnici s dijagnostikovanim BRSS treba da budu redovno praćeni zbog ovakve prirode bolesti.…”