EZH2 promotes neoplastic transformation through VAV interaction-dependent extranuclear mechanisms

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-independ...

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Main 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
Other Authors: School of Computer Science and Engineering
Format: Article
Language:English
Published: 2018
Subjects:
VAV
Online Access:https://hdl.handle.net/10356/87507
http://hdl.handle.net/10220/44455
https://doi.org/10.21979/N9/AJYMP5
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Institution: Nanyang Technological University
Language: English
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Summary: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.