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Title: EZH2 promotes neoplastic transformation through VAV interaction-dependent extranuclear mechanisms
Authors: Venkatesan, Nandini
Wong, Jong Fu
Tan, Kuan Pern
Chung, Hwa Hwa
Yau, Yin Hoe
Cukuroglu, Engin
Allahverdi, Abdollah
Nordenskiold, Lars
Goke, Jonathan
Geifman-Shochat, Susana
Lin, Valerie Chun Ling
Madhusudhan, M. S.
Su, I-hsin
Keywords: EZH2
Issue Date: 2018
Source: Venkatesan, N., Wong, J. F., Tan, K. P., Chung, H. H., Yau, Y. H., Cukuroglu, E., et al. (2017). EZH2 promotes neoplastic transformation through VAV interaction-dependent extranuclear mechanisms. Oncogene, 37(4), 461-477.
Series/Report no.: Oncogene
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.
ISSN: 0950-9232
DOI: 10.1038/onc.2017.309
Rights: © 2018 The Author(s) (Nature Publishing Group). This is the author created version of a work that has been peer reviewed and accepted for publication by Oncogene, The Author(s) (Nature Publishing Group). It incorporates referee’s comments but changes resulting from the publishing process, such as copyediting, structural formatting, may not be reflected in this document. The published version is available at: [].
Fulltext Permission: open
Fulltext Availability: With Fulltext
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