The Histone H3 Lysine 4 Presenter WDR5 as an Oncogenic Protein and Novel Epigenetic Target in Cancer

The histone H3 lysine 4 (H3K4) presenter WDR5 forms protein complexes with H3K4 methyltransferases MLL1-MLL4 and binding partner proteins including RBBP5, ASH2L, and DPY30, and plays a key role in histone H3K4 trimethylation, chromatin remodeling, transcriptional activation of target genes, normal b...

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Published inFrontiers in oncology Vol. 8; p. 502
Main Authors Lu, Kebin, Tao, He, Si, Xiaomin, Chen, Qingjuan
Format Journal Article
LanguageEnglish
Published Switzerland Frontiers Media S.A 14.11.2018
Subjects
cancer therapy
gene transcription
histone H3K4 methylation
MLL
Oncology
tumorigenesis
WDR5
WDR5
cancer therapy
gene transcription
tumorigenesis
MLL
histone H3K4 methylation
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Summary:The histone H3 lysine 4 (H3K4) presenter WDR5 forms protein complexes with H3K4 methyltransferases MLL1-MLL4 and binding partner proteins including RBBP5, ASH2L, and DPY30, and plays a key role in histone H3K4 trimethylation, chromatin remodeling, transcriptional activation of target genes, normal biology, and diseases such as MLL-rearranged leukemia. By forming protein complexes with other proteins such as Myc, WDR5 induces transcriptional activation of key oncogenes, tumor cell cycle progression, DNA replication, cell proliferation, survival, tumor initiation, progression, invasion, and metastasis of cancer of a variety of organ origins. Several small molecule MLL/WDR5 protein-protein interaction inhibitors, such as MM-401, MM-589, WDR5-0103, Piribedil, and OICR-9429, have been confirmed to reduce H3K4 trimethylation, oncogenic gene expression, cell cycle progression, cancer cell proliferation, survival and resistance to chemotherapy without general toxicity to normal cells. Derivatives of the MLL/WDR5 interaction inhibitors with improved pharmacokinetic properties and bioavailability are expected to have the potential to be trialed in cancer patients.
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Edited by: Suzie Chen, Rutgers University, The State University of New Jersey, United States
Reviewed by: Hui-Ju Hsieh, University of Texas MD Anderson Cancer Center, United States; Yun Dai, Virginia Commonwealth University, United States; Brian A. Wall, Colgate Palmolive, United States
This article was submitted to Cancer Molecular Targets and Therapeutics, a section of the journal Frontiers in Oncology
ISSN:2234-943X
2234-943X
DOI:10.3389/fonc.2018.00502