CYLD regulates keratinocyte differentiation and skin cancer progression in humans

J P Alameda,M J Fernández-Aceñero,M Navarro,M L Casanova,R Quintana,A Ramírez,A Page,R Moreno-Maldonado,A Bravo

doi:10.1038/cddis.2011.82

Abstract

CYLD is a gene mutated in familial cylindromatosis and related diseases, leading to the development of skin appendages tumors. Although the deubiquitinase CYLD is a skin tumor suppressor, its role in skin physiology is unknown. Using skin organotypic cultures as experimental model to mimic human skin, we have found that CYLD acts as a regulator of epidermal differentiation in humans through the JNK signaling pathway. We have determined the requirement of CYLD for the maintenance of epidermal polarity, keratinocyte differentiation and apoptosis. We show that CYLD overexpression increases keratinocyte differentiation while CYLD loss of function impairs epidermal differentiation. In addition, we describe the important role of CYLD in the control of human non-melanoma skin cancer progression. Our results show the reversion of the malignancy of human squamous cell carcinomas that express increased levels of CYLD, while its functional inhibition enhances the aggressiveness of these tumors which progress toward spindle cell carcinomas. We have found that the mechanisms through which CYLD regulates skin cancer progression include the control of tumor differentiation, angiogenesis and cell survival. These findings of the role of CYLD in human skin cancer prognosis make our results relevant from a therapeutic point of view, and open new avenues for exploring novel cancer therapies.

Highlights

CYLD is a tumor suppressor gene that was originally identified as a gene mutated in familial cylindromatosis, a genetic condition that predisposes patients for the development of skin appendages tumors.[7]
Our data demonstrate that alterations in CYLD expression in keratinocytes disrupt normal epidermal homeostasis: the forced expression of CYLDWT in human HaCaT keratinocytes and the skin equivalents enhance keratinocyte differentiation
We have found that Jun-NH2-terminal kinase (JNK) signaling pathway could be mediating the effects of CYLD in epidermal differentiation

Summary

Introduction

CYLD is a tumor suppressor gene that was originally identified as a gene mutated in familial cylindromatosis, a genetic condition that predisposes patients for the development of skin appendages tumors.[7]. Besides its role in the familial cylindromatosis, additional studies have associated CYLD downregulation with the development of other types of human cancer including tumors of colon, lung and kidney, as well as melanomas and cervical and hepatocellular carcinomas.[16,17,18,19,20] Recently, we have demonstrated a relationship between the inhibition of CYLD function and an increase in aggressiveness of mouse NMSC.[21] CYLD is ubiquitously expressed and its function as tumor suppressor is being actively investigated, little is known about its role in the homeostasis of the different tissues; in the skin. The epithelium of the skin organotypic culture cells detected by northern blotting at the stated times (days); 7S, loading control. Western blots were performed 3–4 times stratifies and differentiates This model has allowed us to increase the expression or to inhibit the function of CYLD in a human-like context. Using an in vivo xenograft model of skin carcinogenesis, we describe the important role of CYLD in the control of human NMSC progression

Methods

Results

Conclusion