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Inhibition of lysine‐specific histone demethylase LSD1 suppresses melanoma growth
Author(s) -
Lian Christine Guo,
Fang Rui,
Zhan Qian,
Ma Jie,
Lee ChungWei,
Frank Markus H.,
Shi Yujiang Geno,
Murphy George F.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1088.15
Subject(s) - demethylase , gene knockdown , melanoma , cancer research , epigenetics , cell growth , biology , histone , cell culture , chemistry , microbiology and biotechnology , biochemistry , gene , genetics
Lysine‐related histone methylation, a key mechanism of epigenetic regulation, is a reversible event mediated by the lysine‐specific demethylase 1 (LSD1). Here we explored the epigenetic effects of LSD1 inhibition in melanoma. First, the expression of LSD1 was evaluated by RT‐PCR in cultured human melanoma cell lines A2058 and SK‐Mel5 and was found to be significantly higher in the more aggressive line A2058 compared to SK‐Mel5 cells. Next, LSD1 was knocked down in A2058 cells using an adenovirus‐based siRNA delivery system. A cluster of genes including Melan‐A and VEGF, were significantly down‐regulated in LSD1 knockdown A2058 cells. Moreover, melanoma growth in soft agar revealed significant reduction in colony formation by cells treated with LSD1 inhibitors. Finally, LSD1 knockdown A2058 cells demonstrated diminished tumor growth in NOD‐SCID mouse xenografts. Overall, our data reveal that LSD1 inhibition suppressed colony formation in vitro and human‐to‐mouse melanoma xenograft growth in vivo . These findings suggest that repression of LSD1 can suppress melanoma growth, thus providing a rationale for development of targeted LSD1 inhibitors for melanoma therapy. Study funded by NIH‐GM078458 and NIH‐NCI 5P50CA093683–09.