Involvement of the tubulin tyrosine ligase-like family member 4 polyglutamylase in PELP1 polyglutamylation and chromatin remodeling in pancreatic cancer cells

Kotoe Kashiwaya, Hidewaki Nakagawa, Masayo Hosokawa, Yasuo Mochizuki, Koji Ueda, Lianhua Piao, Suyoun Chung, Ryuji Hamamoto, Hidetoshi Eguchi, Hiroaki Ohigashi, Osamu Ishikawa, Carsten Janke, Yasuhisa Shinomura, Yusuke Nakamura

研究成果: ジャーナルへの寄稿学術誌査読

31 被引用数 (Scopus)

抄録

Polyglutamylation is a new class of posttranslational modification in which glutamate side chains are formed in proteins, although its biological significance is not well known. Through our genome-wide gene expression profile analyses of pancreatic ductal adenocarcinoma (PDAC) cells, we identified the overexpression of tubulin tyrosine ligase-like family member 4 (TTLL4) in PDAC cells. Subsequent reverse transcription-PCR and Northern blot analyses confirmed its upregulation in several PDACs. TTLL4 belongs to the TTLL family which was reported to have polyglutamylase activity. Knockdown of TTLL4 by short hairpin RNA in PDAC cells attenuated the growth of PDAC cells and exogenous introduction of TTLL4 enhanced cell growth. We also found that TTLL4 expression was correlated with polyglutamylation levels of a glutamate stretch region of the proline, glutamate, and leucine-rich protein 1 (PELP1) that was shown to interact with various proteins such as histone H3, and was involved in several signaling pathways through its function as a scaffold protein. PELP1 polyglutamylation could influence its interaction with histone H3 and affect histone H3 acetylation. We also identified the interaction of PELP1 with LAS1L and SENP3, components of the MLL1-WDR5 supercomplex involving chromatin remodeling. Our findings imply that TTLL4 could play important roles in pancreatic carcinogenesis through its polyglutamylase activity and subsequent coordination of chromatin remodeling, and might be a good molecular candidate for the development of new therapeutic strategies for pancreatic cancer.

本文言語英語
ページ(範囲)4024-4033
ページ数10
ジャーナルCancer Research
70
10
DOI
出版ステータス出版済み - 5月 15 2010
外部発表はい

!!!All Science Journal Classification (ASJC) codes

  • 腫瘍学
  • 癌研究

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