LOXL1 and LOXL4 Are Epigenetically Silenced and Can Inhibit Ras/Extracellular Signal-Regulated Kinase Signaling Pathway in Human Bladder Cancer

^{1 1}Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins University School of Medicine, and ²Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland; ³Karmanos Cancer Institute, Department of Pathology, Wayne State University, Detroit, Michigan; and ⁴The Collagen Research Unit, Biocenter Oulu and Department of Medical Biochemistry, University of Oulu, Oulu, Finland

^* To whom correspondence should be addressed. E-mail: dsidrans{at}jhmi.edu.

	Abstract

Promoter hypermethylation is one of the common mechanisms leading to gene silencing in various human cancers. Using a combination of pharmacologic unmasking and microarray techniques, we identified 59 candidate hypermethylated genes, including LOXL1, a lysyl oxidase-like gene, in human bladder cancer cells. We further showed that LOXL1 and LOXL4 are commonly silenced genes in human bladder cancer cells, and this silence is predominantly related to promoter methylation. We also found LOXL1 and LOXL4 gene methylation and loss of expression in primary bladder tumors. In addition, somatic mutations were identified in LOXL4, but not in LOXL1 in bladder cancer. Moreover, reintroduction of LOXL1 and LOXL4 genes into human bladder cancer cells leads to a decrease of colony formation ability. Further studies indicated that the overexpression of LOXL1 and LOXL4 could antagonize Ras in activating the extracellular signal-regulated kinase (ERK) signaling pathway. Thus, our current study suggests for the first time that lysyl oxidase-like genes can act as tumor suppressor genes and exert their functions through the inhibition of the Ras/ERK signaling pathway in human bladder cancer. [Cancer Res 2007;67(9):4123-9]

Key Words: LOXL1, LOXL4, Bladder cancer, Methylation, Ras

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