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Research Article

Naturally occurring isothiocyanates exert anticancer effects by inhibiting deubiquitinating enzymes

Ann P Lawson, Marcus JC Long, Rory T Coffey, Yu Qian, Eranthie Weerapana, Farid El Oualid and Lizbeth Hedstrom
Ann P Lawson
1Biology, Brandeis University
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Marcus JC Long
1Biology, Brandeis University
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Rory T Coffey
1Biology, Brandeis University
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Yu Qian
2Department of Chemistry, Boston College
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Eranthie Weerapana
2Department of Chemistry, Boston College
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Farid El Oualid
3UbiQ, UbiQ
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Lizbeth Hedstrom
1Biology, Brandeis University
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  • For correspondence: hedstrom@brandeis.edu
DOI: 10.1158/0008-5472.CAN-15-1544
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Abstract

The anticancer properties of cruciferous vegetables are well known and attributed to an abundance of isothiocyanates (ITCs) such as benzyl ITC (BITC) and phenethyl ITC (PEITC). While many potential targets of ITCs have been proposed, a full understanding of the mechanisms underlying their anticancer activity has remained elusive. Here we report that BITC and PEITC effectively inhibit deubiquitinating enzymes (DUBs), including the enzymes USP9x and UCH37, which are associated with tumorigenesis, at physiologically relevant concentrations and time scales. USP9x protects the anti-apoptotic protein Mcl-1 from degradation, and cells dependent on Mcl-1 were especially sensitive to BITC and PEITC. These ITCs increased Mcl-1 ubiquitination and either ITC treatment or RNAi-mediated silencing of USP9x decreased Mcl-1 levels, consistent with the notion that USP9x is a primary target of ITC activity. These ITCs also increased ubiquitination of the oncogenic fusion protein Bcr-Abl, resulting in degradation under low ITC concentrations and aggregation under high ITC concentrations. USP9x inhibition paralleled the decrease in Bcr-Abl levels induced by ITC treatment, and USP9x silencing was sufficient to decrease Bcr-Abl levels, further suggesting that Bcr-Abl is a USP9x substrate. Overall, our findings suggest that USP9x targeting is critical to the mechanism underpinning the well established anticancer activity of ITC. We propose that the ITC-induced inhibition of DUB may also explain how ITCs affect inflammatory and DNA repair processes, thus offering a unifying theme in understanding the function and useful application of ITCs to treat cancer as well as a variety of other pathological conditions.

  • Received June 8, 2015.
  • Revision received August 24, 2015.
  • Accepted August 31, 2015.
  • Copyright © 2015, American Association for Cancer Research.
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This OnlineFirst version was published on November 5, 2015
doi: 10.1158/0008-5472.CAN-15-1544

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Naturally occurring isothiocyanates exert anticancer effects by inhibiting deubiquitinating enzymes
Ann P Lawson, Marcus JC Long, Rory T Coffey, Yu Qian, Eranthie Weerapana, Farid El Oualid and Lizbeth Hedstrom
Cancer Res November 5 2015 DOI: 10.1158/0008-5472.CAN-15-1544

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Naturally occurring isothiocyanates exert anticancer effects by inhibiting deubiquitinating enzymes
Ann P Lawson, Marcus JC Long, Rory T Coffey, Yu Qian, Eranthie Weerapana, Farid El Oualid and Lizbeth Hedstrom
Cancer Res November 5 2015 DOI: 10.1158/0008-5472.CAN-15-1544
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