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Histone H3K4 Methyltransferases as Targets for Drug-Resistant Cancers.

ABSTRACT: The KMT2 (MLL) family of proteins, including the major histone H3K4 methyltransferase found in mammals, exists as large complexes with common subunit proteins and exhibits enzymatic activity. SMYD, another H3K4 methyltransferase, and SET7/9 proteins catalyze the methylation of several non-histone targets, in addition to histone H3K4 residues. Despite these structural and functional commonalities, H3K4 methyltransferase proteins have specificity for their target genes and play a role in the development of various cancers as well as in drug resistance. In this review, we examine the overall role of histone H3K4 methyltransferase in the development of various cancers and in the progression of drug resistance. Compounds that inhibit protein-protein interactions between KMT2 family proteins and their common subunits or the activity of SMYD and SET7/9 are continuously being developed for the treatment of acute leukemia, triple-negative breast cancer, and castration-resistant prostate cancer. These H3K4 methyltransferase inhibitors, either alone or in combination with other drugs, are expected to play a role in overcoming drug resistance in leukemia and various solid cancers.

SUBMITTER: Yang L

PROVIDER: S-EPMC8301125 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Pax6 is a key regulator of the entire cascade of ocular lens formation through specific binding to promoters and enhancers of batteries of target genes. The promoters and enhancers communicate with each other through DNA looping mediated by multiple protein-DNA and protein-protein interactions and are marked by specific combinations of histone posttranslational modifications (PTMs). Enhancers are distinguished from bulk chromatin by specific modifications of core histone H3, including H3K4me1 and H3K27ac, while promoters show increased H3K4me3 PTM. Previous studies have shown the presence of Pax6 in as much as 1/8 of lens-specific enhancers but a much smaller fraction of tissue-specific promoters. Although Pax6 is known to interact with EP300/p300 histone acetyltransferase responsible for generation of H3K27ac, a potential link between Pax6 and histone H3K4 methylation remains to be established.Here we show that Pax6 co-purifies with H3K4 methyltransferase activity in lens cell nuclear extracts. Proteomic studies show that Pax6 immunoprecipitates with Set1a, Mll1, and Mll2 enzymes, and their associated proteins, i.e., Wdr5, Rbbp5, Ash2l, and Dpy30. ChIP-seq studies using chromatin prepared from mouse lens and cultured lens cells demonstrate that Pax6-bound regions are mostly enriched with H3K4me2 and H3K4me1 in enhancers and promoters, though H3K4me3 marks only Pax6-containing promoters. The shRNA-mediated knockdown of Pax6 revealed down-regulation of a set of direct target genes, including Cap2, Farp1, Pax6, Plekha1, Prox1, Tshz2, and Zfp536. Pax6 knockdown was accompanied by reduced H3K4me1 at enhancers and H3K4me3 at promoters, with little or no changes of the H3K4me2 modifications. These changes were prominent in Plekha1, a gene regulated by Pax6 in both lens and retinal pigmented epithelium.Our study supports a general model of Pax6-mediated recruitment of histone methyltransferases Mll1 and Mll2 to lens chromatin, especially at distal enhancers. Genome-wide data in lens show that Pax6 binding correlates with H3K4me2, consistent with the idea that H3K4me2 PTMs correlate with the binding of transcription factors. Importantly, partial reduction of Pax6 induces prominent changes in local H3K4me1 and H3K4me3 modification. Together, these data open the field to mechanistic studies of Pax6, Mll1, Mll2, and H3K4me1/2/3 dynamics at distal enhancers and promoters of developmentally controlled genes.

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Histone H3K4 Methyltransferases as Targets for Drug-Resistant Cancers.

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