Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

Cancer differentiating agent hexamethylene bisacetamide inhibits BET bromodomain proteins

Nilsson, Lisa M. ; Green, Lydia C. ; Muralidharan, Somsundar Veppil ; Demir, Daǧsu ; Welin, Martin LU ; Bhadury, Joydeep ; Logan, Derek T. LU orcid ; Walse, Björn LU and Nilsson, Jonas A. (2016) In Cancer Research 76(8). p.2376-2383
Abstract

Agents that trigger cell differentiation are highly efficacious in treating certain cancers, but such approaches are not generally effective in most malignancies. Compounds such as DMSO and hexamethylene bisacetamide (HMBA) have been used to induce differentiation in experimental systems, but their mechanisms of action and potential range of uses on that basis have not been developed. Here, we show that HMBA, a compound first tested in the oncology clinic over 25 years ago, acts as a selective bromodomain inhibitor. Biochemical and structural studies revealed an affinity of HMBA for the second bromodomain of BET proteins. Accordingly, both HMBA and the prototype BET inhibitor JQ1 induced differentiation of mouse erythroleukemia cells.... (More)

Agents that trigger cell differentiation are highly efficacious in treating certain cancers, but such approaches are not generally effective in most malignancies. Compounds such as DMSO and hexamethylene bisacetamide (HMBA) have been used to induce differentiation in experimental systems, but their mechanisms of action and potential range of uses on that basis have not been developed. Here, we show that HMBA, a compound first tested in the oncology clinic over 25 years ago, acts as a selective bromodomain inhibitor. Biochemical and structural studies revealed an affinity of HMBA for the second bromodomain of BET proteins. Accordingly, both HMBA and the prototype BET inhibitor JQ1 induced differentiation of mouse erythroleukemia cells. As expected of a BET inhibitor, HMBA displaced BET proteins from chromatin, caused massive transcriptional changes, and triggered cell-cycle arrest and apoptosis in Myc-induced B-cell lymphoma cells. Furthermore, HMBA exerted anticancer effects in vivo in mouse models of Myc-driven B-cell lymphoma. This study illuminates the function of an early anticancer agent and suggests an intersection with ongoing clinical trials of BET inhibitor, with several implications for predicting patient selection and response rates to this therapy and starting points for generating BD2- selective BET inhibitors. Cancer Res; 76(8); 2376-83.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
subject
in
Cancer Research
volume
76
issue
8
pages
8 pages
publisher
American Association for Cancer Research Inc.
external identifiers
  • pmid:26941288
  • scopus:84971014978
ISSN
0008-5472
DOI
10.1158/0008-5472.CAN-15-2721
language
English
LU publication?
no
additional info
Publisher Copyright: © 2016 American Association for Cancer Research.
id
658ca8bc-673b-4a31-a213-59c4aa80780b
date added to LUP
2022-04-25 11:22:28
date last changed
2024-01-03 10:33:53
@article{658ca8bc-673b-4a31-a213-59c4aa80780b,
  abstract     = {{<p>Agents that trigger cell differentiation are highly efficacious in treating certain cancers, but such approaches are not generally effective in most malignancies. Compounds such as DMSO and hexamethylene bisacetamide (HMBA) have been used to induce differentiation in experimental systems, but their mechanisms of action and potential range of uses on that basis have not been developed. Here, we show that HMBA, a compound first tested in the oncology clinic over 25 years ago, acts as a selective bromodomain inhibitor. Biochemical and structural studies revealed an affinity of HMBA for the second bromodomain of BET proteins. Accordingly, both HMBA and the prototype BET inhibitor JQ1 induced differentiation of mouse erythroleukemia cells. As expected of a BET inhibitor, HMBA displaced BET proteins from chromatin, caused massive transcriptional changes, and triggered cell-cycle arrest and apoptosis in Myc-induced B-cell lymphoma cells. Furthermore, HMBA exerted anticancer effects in vivo in mouse models of Myc-driven B-cell lymphoma. This study illuminates the function of an early anticancer agent and suggests an intersection with ongoing clinical trials of BET inhibitor, with several implications for predicting patient selection and response rates to this therapy and starting points for generating BD2- selective BET inhibitors. Cancer Res; 76(8); 2376-83.</p>}},
  author       = {{Nilsson, Lisa M. and Green, Lydia C. and Muralidharan, Somsundar Veppil and Demir, Daǧsu and Welin, Martin and Bhadury, Joydeep and Logan, Derek T. and Walse, Björn and Nilsson, Jonas A.}},
  issn         = {{0008-5472}},
  language     = {{eng}},
  month        = {{04}},
  number       = {{8}},
  pages        = {{2376--2383}},
  publisher    = {{American Association for Cancer Research Inc.}},
  series       = {{Cancer Research}},
  title        = {{Cancer differentiating agent hexamethylene bisacetamide inhibits BET bromodomain proteins}},
  url          = {{http://dx.doi.org/10.1158/0008-5472.CAN-15-2721}},
  doi          = {{10.1158/0008-5472.CAN-15-2721}},
  volume       = {{76}},
  year         = {{2016}},
}