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EZH2 promotes neoplastic transformation through VAV interaction-dependent extranuclear mechanisms.
Venkatesan, N; Wong, J F; Tan, K P; Chung, H H; Yau, Y H; Cukuroglu, E; Allahverdi, A; Nordenskiöld, L; Göke, J; Geifman-Shochat, S; Lin, V C L; Madhusudhan, M S; Su, I-H.
Afiliação
  • Venkatesan N; School of Biological Sciences, College of Science, Nanyang Technological University, Republic of Singapore.
  • Wong JF; School of Biological Sciences, College of Science, Nanyang Technological University, Republic of Singapore.
  • Tan KP; Bioinformatics Institute, Agency for Science, Technology and Research, Biopolis, Republic of Singapore.
  • Chung HH; School of Computer Engineering, Nanyang Technological University, Republic of Singapore.
  • Yau YH; School of Biological Sciences, College of Science, Nanyang Technological University, Republic of Singapore.
  • Cukuroglu E; School of Biological Sciences, College of Science, Nanyang Technological University, Republic of Singapore.
  • Allahverdi A; Genome Institute of Singapore, Agency for Science, Technology and Research, Biopolis, Republic of Singapore.
  • Nordenskiöld L; School of Biological Sciences, College of Science, Nanyang Technological University, Republic of Singapore.
  • Göke J; School of Biological Sciences, College of Science, Nanyang Technological University, Republic of Singapore.
  • Geifman-Shochat S; Genome Institute of Singapore, Agency for Science, Technology and Research, Biopolis, Republic of Singapore.
  • Lin VCL; National Cancer Centre Singapore, Republic of Singapore.
  • Madhusudhan MS; School of Biological Sciences, College of Science, Nanyang Technological University, Republic of Singapore.
  • Su IH; School of Biological Sciences, College of Science, Nanyang Technological University, Republic of Singapore.
Oncogene ; 37(4): 461-477, 2018 01 25.
Article em En | MEDLINE | ID: mdl-28967906
ABSTRACT
Recently, we reported that the histone methyltransferase, EZH2, controls leukocyte migration through interaction with the cytoskeleton remodeling effector, VAV, and direct methylation of the cytoskeletal regulatory protein, Talin. However, it is unclear whether this extranuclear, epigenetic-independent function of EZH2 has a profound impact on the initiation of cellular transformation and metastasis. Here, we show that EZH2 increases Talin1 methylation and cleavage, thereby enhancing adhesion turnover and promoting accelerated tumorigenesis. This transforming capacity is abolished by targeted disruption of EZH2 interaction with VAV. Furthermore, our studies demonstrate that EZH2 in the cytoplasm is closely associated with cancer stem cell properties, and that overexpression of EZH2, a mutant EZH2 lacking its nuclear localization signal (EZH2ΔNLS), or a methyl-mimicking Talin1 mutant substantially promotes JAK2-dependent STAT3 activation and cellular transformation. Taken together, our results suggest a critical role for the VAV interaction-dependent, extranuclear action of EZH2 in neoplastic transformation.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Regulação Neoplásica da Expressão Gênica / Transformação Celular Neoplásica / Proteínas Proto-Oncogênicas c-vav / Proteína Potenciadora do Homólogo 2 de Zeste / Neoplasias Tipo de estudo: Prognostic_studies Idioma: En Revista: Oncogene Assunto da revista: BIOLOGIA MOLECULAR / NEOPLASIAS Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Regulação Neoplásica da Expressão Gênica / Transformação Celular Neoplásica / Proteínas Proto-Oncogênicas c-vav / Proteína Potenciadora do Homólogo 2 de Zeste / Neoplasias Tipo de estudo: Prognostic_studies Idioma: En Revista: Oncogene Assunto da revista: BIOLOGIA MOLECULAR / NEOPLASIAS Ano de publicação: 2018 Tipo de documento: Article