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Controlled inhibition of methyltransferases using photoswitchable peptidomimetics: towards an epigenetic regulation of leukemia.

ABSTRACT: We describe a cell-permeable photoswitchable probe capable of modulating epigenetic cellular states by disruption of an essential protein-protein interaction within the MLL1 methyltransferase core complex. Our azobenzene-containing peptides selectively block the WDR5-MLL1 interaction by binding to WDR5 with high affinity (Ki = 1.25 nM). We determined the co-crystal structure of this photoswitchable peptiomimetic with WDR5 to understand the interaction at the atomic level. Importantly, the photoswitchable trans and cis conformers of the probe display a clear difference in their inhibition of MLL1. We further demonstrate that the designed photo-controllable azo-peptidomimetics affect the transcription of the MLL1-target gene Deptor, which regulates hematopoiesis and leukemogenesis, and inhibit the growth of leukemia cells. This strategy demonstrates the potential of photopharmacological inhibition of methyltransferase protein-protein interactions as a novel method for external epigenetic control, providing a new toolbox for controlling epigenetic states.

SUBMITTER: Albert L

PROVIDER: S-EPMC5618341 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Controlled inhibition of methyltransferases using photoswitchable peptidomimetics: towards an epigenetic regulation of leukemia.

Albert Lea L Xu Jing J Wan Ruiwei R Srinivasan Vasundara V Dou Yali Y Vázquez Olalla O

Chemical science 20170427 6

We describe a cell-permeable photoswitchable probe capable of modulating epigenetic cellular states by disruption of an essential protein-protein interaction within the MLL1 methyltransferase core complex. Our azobenzene-containing peptides selectively block the WDR5-MLL1 interaction by binding to WDR5 with high affinity (<i>K</i><sub>i</sub> = 1.25 nM). We determined the co-crystal structure of this photoswitchable peptiomimetic with WDR5 to understand the interaction at the atomic level. Impor ...[more]

PMID: 28970883

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Project description:Dysregulation of PML, a significant tumor suppressor is linked with cancers of different histological origins, with a decreased expression observed with a higher tumor grade. This necessitates studying the mechanisms to maintain a stable expression of PML. However much less is known about the transcriptional regulation of PML, more so in the context of breast carcinoma. ERβ has emerged as a critical factor in understanding breast cancer, especially since a huge proportion of breast cancers are ERα- and thus insensitive to tamoxifen therapy. This study aims to uncover an unidentified mechanism of PML gene regulation and its stabilization in breast cancer via ERβ signalling and the impact on cellular apoptosis. We found that clinical expression of PML positively correlates with that of ERβ both in normal and breast carcinoma samples and inversely correlates with markers of cellular proliferation, hinting towards a possible mechanistic interdependence. Both mRNA and protein expression of PML were increased in response to ERβ overexpression on multiple human breast cancer cell lines. Mechanistically, luciferase reporter assays and chromatin-immunoprecipitation assays demonstrated that ERβ can interact with the PML promoter via ERE and AP1 sites to enhance its transcription. ERβ induced stable PML expression causes a decline of its target protein Survivin and simultaneously provides a stable docking platform leading to stabilisation of its target Foxo3a, further causing transcriptional upregulation of pro-apoptotic factors p21 and p27. Immunohistochemical analyses of cancer and normal breast tissues and functional assays conducted corroborated the findings. Collectively, our study identifies ERβ signalling as a novel mechanism for PML gene regulation in ERα- breast cancer. It also reveals bi-directional downstream effect in which 'ERβ-PML-(Foxo3a/Survivin)' network acts as a therapeutic axis by suppressing cellular survival and promoting cellular apoptosis in breast carcinoma.

Dataset Information

Controlled inhibition of methyltransferases using photoswitchable peptidomimetics: towards an epigenetic regulation of leukemia.

Publications

Controlled inhibition of methyltransferases using photoswitchable peptidomimetics: towards an epigenetic regulation of leukemia.

Similar Datasets

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