Acta Dermato-Venereologica 99-1CompleteContent | Page 18

INVESTIGATIVE REPORT 63 Expression of n-MYC, NAMPT and SIRT1 in Basal Cell Carcinomas and their Cells of Origin Lydia BRANDL 1 , Daniela HARTMANN 2 , Thomas KIRCHNER 1,3 and Antje MENSSEN 1 Institute of Pathology, 2 Department of Dermatology and Allergology, Ludwig-Maximilians University, Munich, and 3 German Consortium for Translational Cancer Research (DKTK), DKFZ, Heidelberg, DKTK Site, Munich, Germany 1 Deregulated Hedgehog signalling is a driver of basal cell carcinomas. One effector of the Hedgehog pathway is n-MYC. c/n-MYC proteins, NAMPT and DBC1 are linked to SIRT1 in a positive feedback loop that may contribute to tumorigenesis of basal cell carcinoma. In 5 basal cell carcinoma types immunohistochemistry re- vealed n-MYC, NAMPT and SIRT1 expression. DBC1 was homogenously expressed in all epithelial cells. NAMPT, SIRT1 and c-MYC were expressed in the stratum basale of human and murine skin. In hair follicles NAMPT and SIRT1 were expressed together with c-MYC and n-MYC, except for the matrix, where n-MYC was strongly po- sitive, but c-MYC expression was absent. Therefore, a common pathway connecting n-MYC, NAMPT and SIRT1 may be active in basal cell carcinomas and in their cells of origin. This pathway may contribute to the develop- ment of basal cell carcinomas. Targeting factors in the feedback loop may offer novel therapeutic options. Key words: basal cell carcinoma; hair follicle stem cells; MYC; NAMPT; SIRT1. Accepted Sep 4, 2018; Epub ahead of print Sep 5, 2018 Acta Derm Venereol 2019; 99: 63–71. Corr: Antje Menssen, Institute of Pathology, Ludwig-Maximilians Univer- sity, Munich, Thalkirchnerstr. 36, DE-80337 Munich, Germany. E-mail: [email protected] T he Hedgehog (Hh) pathway harbours prevalent so- matic mutations and is a central driver of basal cell carcinoma (BCC) development. These mutations include loss-of-function mutations in the Hh receptor Patched 1 (PTCH1) gene (73%), or activating mutations in Smoothe- ned (SMO) (20%)). Furthermore, BCCs typically harbour mutations in the Hippo-YAP pathway (PTPN14 (23%), LATS1 (16%)), and in TP53 (61%), the hTERT promoter, and in the DPH3-OXNAD1 bidirectional promoter (42%). Recently, additional oncogenic alterations have been un- covered that explained the heterogeneous nature of BCCs (reviewed in (1)). Hair follicle (HF) stem cells have been postulated to represent the cell of origin of BCC, since they share many characteristics with BCCs. In addition, interfollicular epidermis (IFE) progenitor cells may give rise to BCCs (2, 3). An important downstream mediator of Hh signalling is the n-MYC proto-oncogene protein (4), which is activated by Hh-induced transcriptional and post-transcriptional mechanisms (5–7). Since the Hh and Wnt pathways are connected through cross-regulation (8), Wnt pathway SIGNIFICANCE Basal cell carcinoma is a skin tumour with locally aggres- sive growth. Analysing human basal cell carcinomas, and human and murine normal skin, including hair follicles, we show that the proteins of the c-MYC-NAMPT-DBC1-SIRT1 positive feedback loop may be active in both the skin stem cell areas, which are considered the cells of origin, and in basal cell carcinomas. Therefore, the positive feedback loop may play a crucial role in the development of basal cell carcinomas. Since NAMPT and SIRT are targetable en- zymes, our results may open novel avenues for therapeutic interventions in basal cell carcinomas. activation may also contribute to BCCs by transcriptional induction of the β-catenin/TCF4 target gene MYCN. We, and others, have shown that the constitutive activation of the Wnt pathway in BCCs is reflected by the accumula- tion, stabilization and nuclear translocation of β-catenin, and nuclear LEF1 expression (9, 10). n-MYC and c-MYC belong to the MYC family of trans- cription factors. They have an homologous amino acid sequence in functionally relevant domains and they share the same canonical E-box DNA motives, overlapping target genes and many functions (11, 12). MYC proteins regulate processes associated with proliferation, such as the regulation of cell cycle entry, DNA replication, protein synthesis, block of differentiation and metabolism. De- regulation of MYC proteins is a common feature of most cancers (reviewed in (13)). We, and others have shown that the NAD + -dependent deacetylase silent information regulator 1 (SIRT1) is downstream of c-MYC, and of n-MYC (14, 15). SIRT1 is involved in the regulation of transcription, apoptosis, DNA damage repair, metabolism, and triggers resistance to cellular stressors, such as DNA damage, oxidative stress and fasting (16). While various pro-apoptotic factors, including p53, are negatively regu- lated by SIRT1, SIRT1 is linked to c-MYC and n-MYC through a positive feedback loop. The SIRT1 protein is overexpressed in the majority of solid and haematopoietic malignancies. It acts as a survival factor for cancer cells and cancer stem cells and contributes to tumour cell drug resistance. An important function of SIRT1 in cancer may be to counteract apoptosis, senescence and cell cycle ar- rest, thus supporting survival and permanent tumour cell proliferation (reviewed in (16–18)). We identified the NAD + salvage pathway enzyme nicotinamide phosphori- This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2019 Acta Dermato-Venereologica. doi: 10.2340/00015555-3031 Acta Derm Venereol 2019; 99: 63–71