TY - JOUR
T1 - A mutation in histone H2B represents a new class of oncogenic driver
AU - Bennett, Richard L.
AU - Bele, Aditya
AU - Small, Eliza C.
AU - Will, Christine M.
AU - Nabet, Behnam
AU - Oyer, Jon A.
AU - Huang, Xiaoxiao
AU - Ghosh, Rajarshi P.
AU - Grzybowski, Adrian T.
AU - Yu, Tao
AU - Zhang, Qiao
AU - Riva, Alberto
AU - Lele, Tanmay P.
AU - Schatz, George C.
AU - Kelleher, Neil L.
AU - Ruthenburg, Alexander J.
AU - Liphardt, Jan
AU - Licht, Jonathan D.
N1 - Funding Information:
This study was supported by Physical Science of Oncology grant U54CA143869 (J.D. Licht), R01GM115945 (A.J. Ruthenburg), American Cancer Society 130230-RSG-16-248-01-DMC (A.J. Ruthenburg), R01EB014869 (T.P. Lele), American Cancer Society Postdoctoral Fellowship PF-17-010-01-CDD (B. Nabet), and the Harper Dissertation Prize and Dean?s International Student Fellowship from the University of Chicago (A.T. Grzybowski).
Funding Information:
J.A. Oyer is principal scientist at Pfizer Inc. and senior scientist II at AbbVie Inc., and has ownership interest (including stock, patents, etc.) in Pfizer Inc. and AbbVie Inc. A.J. Ruthenburg is a consultant/ advisory board member for Epicypher Inc. J.D. Licht is chief scientific officer at the Samuel Waxman Cancer Research Foundation and reports receiving a commercial research grant from Celgene. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
This study was supported by Physical Science of Oncology grant U54CA143869 (J.D. Licht), R01GM115945 (A.J. Ruthenburg), American Cancer Society 130230-RSG-16-248-01-DMC (A.J. Ruthenburg), R01EB014869 (T.P. Lele), American Cancer Society Postdoctoral Fellowship PF-17-010-01-CDD (B. Nabet), and the Harper Dissertation Prize and Dean’s International Student Fellowship from the University of Chicago (A.T. Grzybowski).
PY - 2019/10
Y1 - 2019/10
N2 - By examination of the cancer genomics database, we identified a new set of mutations in core histones that frequently recur in cancer patient samples and are predicted to disrupt nucleosome stability. In support of this idea, we characterized a glutamate to lysine mutation of histone H2B at amino acid 76 (H2B-E76K), found particularly in bladder and head and neck cancers, that disrupts the interaction between H2B and H4. Although H2B-E76K forms dimers with H2A, it does not form stable histone octamers with H3 and H4 in vitro, and when reconstituted with DNA forms unstable nucleosomes with increased sensitivity to nuclease. Expression of the equivalent H2B mutant in yeast restricted growth at high temperature and led to defective nucleosome-mediated gene repression. Significantly, H2B-E76K expression in the normal mammary epithelial cell line MCF10A increased cellular proliferation, cooperated with mutant PIK3CA to promote colony formation, and caused a significant drift in gene expression and fundamental changes in chromatin accessibility, particularly at gene regulatory elements. Taken together, these data demonstrate that mutations in the globular domains of core histones may give rise to an oncogenic program due to nucleosome dysfunction and deregulation of gene expression. SIGNIFICANCE: Mutations in the core histones frequently occur in cancer and represent a new mechanism of epigenetic dysfunction that involves destabilization of the nucleosome, deregulation of chromatin accessibility, and alteration of gene expression to drive cellular transformation.
AB - By examination of the cancer genomics database, we identified a new set of mutations in core histones that frequently recur in cancer patient samples and are predicted to disrupt nucleosome stability. In support of this idea, we characterized a glutamate to lysine mutation of histone H2B at amino acid 76 (H2B-E76K), found particularly in bladder and head and neck cancers, that disrupts the interaction between H2B and H4. Although H2B-E76K forms dimers with H2A, it does not form stable histone octamers with H3 and H4 in vitro, and when reconstituted with DNA forms unstable nucleosomes with increased sensitivity to nuclease. Expression of the equivalent H2B mutant in yeast restricted growth at high temperature and led to defective nucleosome-mediated gene repression. Significantly, H2B-E76K expression in the normal mammary epithelial cell line MCF10A increased cellular proliferation, cooperated with mutant PIK3CA to promote colony formation, and caused a significant drift in gene expression and fundamental changes in chromatin accessibility, particularly at gene regulatory elements. Taken together, these data demonstrate that mutations in the globular domains of core histones may give rise to an oncogenic program due to nucleosome dysfunction and deregulation of gene expression. SIGNIFICANCE: Mutations in the core histones frequently occur in cancer and represent a new mechanism of epigenetic dysfunction that involves destabilization of the nucleosome, deregulation of chromatin accessibility, and alteration of gene expression to drive cellular transformation.
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UR - http://www.scopus.com/inward/citedby.url?scp=85072849154&partnerID=8YFLogxK
U2 - 10.1158/2159-8290.CD-19-0393
DO - 10.1158/2159-8290.CD-19-0393
M3 - Article
C2 - 31337617
AN - SCOPUS:85072849154
VL - 9
SP - 1438
EP - 1451
JO - Cancer Discovery
JF - Cancer Discovery
SN - 2159-8274
IS - 10
ER -