PXD010842

PXD010842 is an original dataset announced via ProteomeXchange.

Title	Targeting Histone Modification Crosstalk as a Therapeutic Strategy for EZH2-aberrant Solid Tumors
Description	Mutations or aberrant upregulation of the histone methyltransferase EZH2 occur frequently in human cancers yet EZH2-targeted therapies have only shown very limited clinical benefits in hematological malignancies. We report here that upon EZH2 inhibition, MLL1 interacts with p300/CBP complex that directs H3K27me loss to gain of H3K27ac modification. This histone modification crosstalk leads to transcriptional reprogramming that restricts the therapeutic response to EZH2 inhibition. Concurrent inhibition of H3K27 methylation and acetylation results in transcriptional repression and growth dependency on the MAPK signaling pathway in a large cancer subset. In pre-clinical models encompassing a broad spectrum of EZH2-aberrant solid tumors, a combination of EZH2 and BRD4 inhibitors or a triple-combination including MAPK inhibition display robust efficacy with tolerable toxicity, in particular in liver and pancreatic cancers. Our results suggest an attractive precision treatment and patient stratification strategy for EZH2-aberrant tumors on the basis of intrinsic MLL1 expression and feedback MAPK activation.
HostingRepository	iProX
AnnounceDate	2018-09-10
AnnouncementXML	Submission_2019-06-17_21:16:56.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Min Zhang
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	phosphorylated residue; acetylated residue; TMT6plex reporter fragment
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2018-08-21 22:45:26	ID requested
1	2018-09-11 18:56:44	announced
⏵ 2	2019-06-17 21:16:58	announced	Update publication information.

Huang X, Yan J, Zhang M, Wang Y, Chen Y, Fu X, Wei R, Zheng XL, Liu Z, Zhang X, Yang H, Hao B, Shen YY, Su Y, Cong X, Huang M, Tan M, Ding J, Geng M, Targeting Epigenetic Crosstalk as a Therapeutic Strategy for EZH2-Aberrant Solid Tumors. Cell, 175(1):186-199.e19(2018) [pubmed]

submitter keyword: EZH2, H3K27ac, LC-MS/MS

Minjia Tan
contact affiliation	Shanghai Institute of Materia Medica
contact email	mjtan@simm.ac.cn
lab head
Min Zhang
contact affiliation	Shanghai Institute of Materia Medica
contact email	zhangmin1990sjtu@163.com
dataset submitter

iProX dataset URI