Open AccessEffects of SMYD 2‐mediated EML 4‐ ALK methylation on the signaling pathway and growth in non‐small‐cell lung cancer cells
Author(s) -
Wang Rui,
Deng Xiaolan,
Yoshioka Yuichiro,
Vougiouklakis Theodore,
Park JaeHyun,
Suzuki Takehiro,
Dohmae Naoshi,
Ueda Koji,
Hamamoto Ryuji,
Nakamura Yusuke
Publication year - 2017
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13245
Subject(s) - anaplastic lymphoma kinase , methylation , cancer research , methyltransferase , cell growth , alk inhibitor , biology , microbiology and biotechnology , protein kinase b , phosphorylation , chemistry , lung cancer , biochemistry , gene , medicine , malignant pleural effusion
A specific subtype of non‐small‐cell lung cancer ( NSCLC ) characterized with an EML 4‐ ALK fusion gene, which drives constitutive oncogenic activation of anaplastic lymphoma kinase ( ALK ), shows a good clinical response to ALK inhibitors. We have reported multiple examples implying the biological significance of methylation on non‐histone proteins including oncogenic kinases in human carcinogenesis. Through the process to search substrates for various methyltransferases using an in vitro methyltransferase assay, we found that a lysine methyltransferase, SET and MYND domain‐containing 2 ( SMYD 2), could methylate lysine residues 1451, 1455, and 1610 in ALK protein. Knockdown of SMYD 2 as well as treatment with a SMYD 2 inhibitor in two NSCLC cell lines with an EML 4‐ ALK gene significantly attenuated the phosphorylation levels of the EML 4‐ ALK protein. Substitutions of each of these three lysine residues to an alanine partially or almost completely diminished in vitro methylation of ALK . In addition, we found that exogenous introduction of EML 4‐ ALK protein with the substitution of lysine 1610 to an alanine in these two cell lines reduced the phosphorylation levels of AKT , one of the downstream oncogenic molecules in the EML 4‐ ALK pathway, and suppressed the growth of the two cell lines. We further showed that the combination of a SMYD 2 inhibitor and an ALK inhibitor additively suppressed the growth of these two NSCLC cells, compared with single‐agent treatment. Our results shed light on a novel mechanism that modulates the kinase activity of the ALK fused gene product and imply that SMYD 2‐mediated ALK methylation might be a promising target for development of a novel class of treatment for tumors with the ALK fused gene.