Chemical inhibitors targeting histone methylation readers

Huang, Xiaolei; Chen, Yichang; Xiao, Qin; Shang, Xinci; Liu, Yanli

doi:10.1016/j.pharmthera.2024.108614

Cited by 2 publications

(4 citation statements)

References 188 publications

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“…Notably, ectopic expression of the WDR5-2A mutant partially rescued cell proliferation and the tumor-promoting effect owing to the retention of the WBM (WDR5-binding motif) site, which interacts with other oncoproteins such as MYC [ 23 ]. Furthermore, in addition to PTENα, WDR5 also interacts with various proteins through its WIN site and these interactions are extensively reported to be involved in tumor progression [ 40 , 41 ]. Thus, this phenotype cannot be attributed solely to the loss of interaction with PTENα/β alone.…”

Section: Resultsmentioning

confidence: 99%

“…In vitro and in vivo studies revealed that the SSSRRSS fragment is indispensable for the pro-tumor activity of PTENα, while the F133/F263 residues of WDR5, essential for the interaction with PTENα/β and other WIN site ligands, are necessary but not the only requirement for the pro-tumor activity of WDR5. In fact, WDR5 also interacts with MYC, a well-known oncoprotein broadly overexpressed in some cancers, through its WBM site to promote tumorigenesis [ 23 ], and other proteins through its WIN site and these interactions are extensively reported to be involved in tumor progression [ 40 , 41 ]. As PTENα and PTENβ share the same SSSRRSS fragment, our findings regarding PTENα are also applicable to PTENβ.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, overexpression of WDR5 is not only associated with the development and progression of various cancers, such as prostate cancer [ 35 , 36 ], breast cancer [ 37 ], leukemia [ 38 ], and liver cancer [ 39 ], but also linked to unfavorable clinical outcomes. Both the WIN site and WBM site are involved in cancer progression [ 40 , 41 ]. Consequently, it appears to be a promising approach for treatment of these diseases by targeting WDR5.…”

Section: Introductionmentioning

confidence: 99%

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The NTE domain of PTENα/β promotes cancer progression by interacting with WDR5 via its SSSRRSS motif

Huang,

Zhang,

Shang

et al. 2024

Cell Death Dis

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PTENα/β, two variants of PTEN, play a key role in promoting tumor growth by interacting with WDR5 through their N-terminal extensions (NTEs). This interaction facilitates the recruitment of the SET1/MLL methyltransferase complex, resulting in histone H3K4 trimethylation and upregulation of oncogenes such as NOTCH3, which in turn promotes tumor growth. However, the molecular mechanism underlying this interaction has remained elusive. In this study, we determined the first crystal structure of PTENα-NTE in complex with WDR5, which reveals that PTENα utilizes a unique binding motif of a sequence SSSRRSS found in the NTE domain of PTENα/β to specifically bind to the WIN site of WDR5. Disruption of this interaction significantly impedes cell proliferation and tumor growth, highlighting the potential of the WIN site inhibitors of WDR5 as a way of therapeutic intervention of the PTENα/β associated cancers. These findings not only shed light on the important role of the PTENα/β-WDR5 interaction in carcinogenesis, but also present a promising avenue for developing cancer treatments that target this pathway.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The NTE domain of PTENα/β promotes cancer progression by interacting with WDR5 via its SSSRRSS motif

Huang,

Zhang,

Shang

et al. 2024

Cell Death Dis

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“…Histone methylation, which occurs on the amino terminal arginine or lysine residues of H3 and H4 histones, is a significant biochemical process (Huang et al, 2024). This methylation is mainly facilitated by histone methyltransferase (HMT), which can be further categorized into histone lysine methyltransferase (HKMT) and protein arginine methyltransferase (PRMT) (Patnaik et al, 2023).…”

Section: Histone Methylation Modificationmentioning

confidence: 99%

Research progress and applications of epigenetic biomarkers in cancer

Gao,

Shi,

Wang

et al. 2024

Front. Pharmacol.

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Epigenetic changes are heritable changes in gene expression without changes in the nucleotide sequence of genes. Epigenetic changes play an important role in the development of cancer and in the process of malignancy metastasis. Previous studies have shown that abnormal epigenetic changes can be used as biomarkers for disease status and disease prediction. The reversibility and controllability of epigenetic modification changes also provide new strategies for early disease prevention and treatment. In addition, corresponding drug development has also reached the clinical stage. In this paper, we will discuss the recent progress and application status of tumor epigenetic biomarkers from three perspectives: DNA methylation, non-coding RNA, and histone modification, in order to provide new opportunities for additional tumor research and applications.

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Chemical inhibitors targeting histone methylation readers

Cited by 2 publications

References 188 publications

The NTE domain of PTENα/β promotes cancer progression by interacting with WDR5 via its SSSRRSS motif

The NTE domain of PTENα/β promotes cancer progression by interacting with WDR5 via its SSSRRSS motif

Research progress and applications of epigenetic biomarkers in cancer

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