Lysyl oxidase‐like 2 represses Notch1 expression in the skin to promote squamous cell carcinoma progression

• Published in: The EMBO journal 2015-04, Vol.34 (8), p.1090-1109
• Main Authors: Martin, Alberto, Salvador, Fernando, Moreno‐Bueno, Gema, Floristán, Alfredo, Ruiz‐Herguido, Cristina, Cuevas, Eva P, Morales, Saleta, Santos, Vanesa, Csiszar, Katalin, Dubus, Pierre, Haigh, Jody J, Bigas, Anna, Portillo, Francisco, Cano, Amparo
• Format: Article
• Language: English
• Subjects: Amino Acid Oxidoreductases - genetics; Amino Acid Oxidoreductases - physiology; Animals; Animals, Newborn; Carcinogenesis; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - pathology; Cell Transformation, Neoplastic - genetics; Cells, Cultured; Disease Progression; Down-Regulation; EMBO03; EMBO11; Enzymes; epidermal differentiation; Female; Gene expression; Gene Expression Regulation, Neoplastic; Genetics; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - pathology; HEK293 Cells; Humans; Loxl2 mouse models; Male; Male sterility; Mice; Mice, Knockout; Notch1; Physiology; Receptor, Notch1 - genetics; Skin cancer; Skin Neoplasms - genetics; Skin Neoplasms - pathology; squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck; Tumors
• ISSN: 0261-4189; 1460-2075
• DOI: 10.15252/embj.201489975

Lysyl oxidase‐like 2 (LOXL2) is involved in a wide range of physiological and pathological processes, including fibrosis and tumor progression, implicating intracellular and extracellular functions. To explore the specific in vivo role of LOXL2 in physiological and tumor contexts, we generated conditional gain‐ and loss‐of‐function mouse models. Germ‐line deletion of Loxl2 promotes lethality in half of newborn mice mainly associated to congenital heart defects, while Loxl2 overexpression triggers male sterility due to epididymal dysfunction caused by epithelial disorganization, fibrosis and acute inflammation. Remarkably, when challenged to chemical skin carcinogenesis, Loxl2‐ overexpressing mice increased tumor burden and malignant progression, while Loxl2 ‐deficient mice exhibit the opposite phenotypes. Loxl2 levels in premalignant tumors negatively correlate with expression of epidermal differentiation markers and components of the Notch1 pathway. We show that LOXL2 is a direct repressor of NOTCH1 . Additionally, we identify an exclusive expression pattern between LOXL2 and members of the canonical NOTCH1 pathway in human HNSCC. Our data identify for the first time novel LOXL2 roles in tissue homeostasis and support it as a target for SCC therapy. Synopsis In vivo genetic analysis of LOXL2 evidences fundamental roles during mouse development. Importantly, mice challenged by a chemical skin carcinogenesis protocol uncover a role for LOXL2 in NOTCH1 inhibition for carcinoma progression. Deletion of Loxl2 causes perinatal lethality due to heart failure and/or distended hepatic capillaries in almost half of dead animals. Overexpression of Loxl2 provokes male sterility due to epididymal dysfunction. Loxl2 overexpression promotes mouse skin tumor progression by negative regulation of epidermal differentiation and Notch1 signaling. LOXL2 directly represses NOTCH1 promoter and cooperates with KLF4. Graphical Abstract In vivo genetic analysis of LOXL2 evidences fundamental roles during mouse development. Importantly, mice challenged by a chemical skin carcinogenesis protocol uncover a role for LOXL2 in NOTCH1 inhibition for carcinoma progression.