TY - JOUR
T1 - Cross-talk between chromatin acetylation and SUMOylation of tripartite motif–containing protein 24 (TRIM24) impacts cell adhesion
AU - Appikonda, Srikanth
AU - Thakkar, Kaushik N.
AU - Shah, Parantu K.
AU - Dent, Sharon Y.R.
AU - Andersen, Jannik N.
AU - Barton, Michelle C.
N1 - Funding Information:
This work was supported in part by CPRIT RP110471 and an Innovation Award from the Center for Cancer Epigenetics (to M. C. B.) and University of Texas M. D. Anderson Cancer Center NCI, National Institutes of Health, Support Grant CA016672. The authors declare that they have no conflicts of interest with the contents of this article. 2 Supported by CPRIT Research Training Award RP140106. Present address: Dept. of Radiation Oncology, Stanford University, 875 Blake Wilbur Dr., Stanford, CA 94305.
Funding Information:
This work was supported in part by CPRIT RP110471 and an Innovation Award from the Center for Cancer Epigenetics (to M. C. B.) and University of Texas M. D. Anderson Cancer Center NCI, National Institutes of Health, Support Grant CA016672. The authors declare that they have no conflicts of interest with the contents of this article. This article was selected as one of our Editors’ Picks. This article contains Tables S1–S4. RNA-Seq data can be accessed at the NCBI gene expression omnibus (GEO) under accession number GSE77140. 1 Present address: Counsyl, 180 Kimball Way, South San Francisco, CA 94080. 2Supported by CPRIT Research Training Award RP140106. Present address: Dept. of Radiation Oncology, Stanford University, 875 Blake Wilbur Dr., Stanford, CA 94305. 3 Present address: EMD Serono Research and Development Institute, Inc., 45A Middlesex Turnpike Billerica, MA 01821. 4Present address: Xios Therapeutics, 465 Waverley Oaks Rd., Waltham, MA 02452. 5To whom correspondence should be addressed: Dept. of Epigenetics and Molecular Carcinogenesis, Unit 1011, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Tel.: 713-834-6268; E-mail: mbarton@mdanderson.org.
Publisher Copyright:
© 2018 Appikonda et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2018/5/11
Y1 - 2018/5/11
N2 - Proteins with domains that recognize and bind post-translational modifications (PTMs) of histones are collectively termed epigenetic readers. Numerous interactions between specific reader protein domains and histone PTMs and their regulatory outcomes have been reported, but little is known about how reader proteins may in turn be modulated by these interactions. Tripartite motif– containing protein 24 (TRIM24) is a histone reader aberrantly expressed in multiple cancers. Here, our investigation revealed functional cross-talk between histone acetylation and TRIM24 SUMOylation. Binding of TRIM24 to chromatin via its tandem PHD-bromodomain, which recognizes unmethylated lysine 4 and acetylated lysine 23 of histone H3 (H3K4me0/K23ac), led to TRIM24 SUMOylation at lysine residues 723 and 741. Inactivation of the bromodomain, either by mutation or with a small-molecule inhibitor, IACS-9571, abolished TRIM24 SUMOylation. Conversely, inhibition of histone deacetylation markedly increased TRIM24’s interaction with chromatin and its SUMOylation. Of note, gene expression profiling of MCF7 cells expressing WT versus SUMO-deficient TRIM24 identified cell adhesion as the major pathway regulated by the cross-talk between chromatin acetylation and TRIM24 SUMOylation. In conclusion, our findings establish a new link between histone H3 acetylation and SUMOylation of the reader protein TRIM24, a functional connection that may bear on TRIM24’s oncogenic function and may inform future studies of PTM cross-talk between histones and epigenetic regulators.
AB - Proteins with domains that recognize and bind post-translational modifications (PTMs) of histones are collectively termed epigenetic readers. Numerous interactions between specific reader protein domains and histone PTMs and their regulatory outcomes have been reported, but little is known about how reader proteins may in turn be modulated by these interactions. Tripartite motif– containing protein 24 (TRIM24) is a histone reader aberrantly expressed in multiple cancers. Here, our investigation revealed functional cross-talk between histone acetylation and TRIM24 SUMOylation. Binding of TRIM24 to chromatin via its tandem PHD-bromodomain, which recognizes unmethylated lysine 4 and acetylated lysine 23 of histone H3 (H3K4me0/K23ac), led to TRIM24 SUMOylation at lysine residues 723 and 741. Inactivation of the bromodomain, either by mutation or with a small-molecule inhibitor, IACS-9571, abolished TRIM24 SUMOylation. Conversely, inhibition of histone deacetylation markedly increased TRIM24’s interaction with chromatin and its SUMOylation. Of note, gene expression profiling of MCF7 cells expressing WT versus SUMO-deficient TRIM24 identified cell adhesion as the major pathway regulated by the cross-talk between chromatin acetylation and TRIM24 SUMOylation. In conclusion, our findings establish a new link between histone H3 acetylation and SUMOylation of the reader protein TRIM24, a functional connection that may bear on TRIM24’s oncogenic function and may inform future studies of PTM cross-talk between histones and epigenetic regulators.
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U2 - 10.1074/jbc.RA118.002233
DO - 10.1074/jbc.RA118.002233
M3 - Article
C2 - 29523690
AN - SCOPUS:85046961646
VL - 293
SP - 7476
EP - 7485
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 19
ER -