Cancer differentiating agent hexamethylene bisacetamide inhibits BET bromodomain proteins
(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.
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- author
- Nilsson, Lisa M. ; Green, Lydia C. ; Muralidharan, Somsundar Veppil ; Demir, Daǧsu ; Welin, Martin LU ; Bhadury, Joydeep ; Logan, Derek T. LU ; Walse, Björn LU and Nilsson, Jonas A.
- publishing date
- 2016-04-15
- 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}}, }