LOXL1 and LOXL4 are epigenetically silenced and can inhibit ras/extracellular signal-regulated kinase signaling pathway in human bladder cancer.
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.
Wu
Guojun
G
Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. wugu@karmanos.org
Guo
Zhongmin
Z
Chang
Xiaofei
X
Kim
Myoung Sook
MS
Nagpal
Jatin K
JK
Liu
Junwei
J
Maki
Joni M
JM
Kivirikko
Kari I
KI
Ethier
Stephen P
SP
Trink
Barry
B
Sidransky
David
D
D000594:Amino Acid Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000201:enzymology; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D044127:Epigenesis, Genetic; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D020868:Gene Silencing; D006801:Humans; D020935:MAP Kinase Signaling System; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000201:enzymology / Q000473:pathology; D008249:Protein-Lysine 6-Oxidase; D001749:Urinary Bladder Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000077209:Decitabine; D000594:Amino Acid Oxidoreductases; C445313:LOXL1 protein, human; C445682:LOXL4 protein, human; D008249:Protein-Lysine 6-Oxidase; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins; D001374:Azacitidine