Specific inhibition of DPY30 activity by ASH2L-derived peptides suppresses blood cancer cell growth

Shah, Kushani; Whitaker, Robert H.; Busby, Theodore; Hu, Jing; Shi, Bi; Wang, Zhenjia; Zang, Chongzhi; Placzek, William J.; Jiang, Hao

doi:10.1016/j.yexcr.2019.06.030

Cited by 20 publications

(14 citation statements)

References 65 publications

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“…Considering its currently limited inhibitors including ASH2L-derived peptides, the question is how to find eligible inhibitors to target Dpy30. 83 , 84 Similarly, another core subunit of chromatin remodeler, namely BPTF, is also a necessary component for the activation of the complete Myc transcription activity in fibroblasts. 85 Moreover, BPTF expression positively correlates with MYC -induced transcriptome signatures in multiple cancer types in humans, such as BL, colorectal, prostate, and pancreatic carcinomas.…”

Section: Alternative Methods To Target Mycmentioning

confidence: 99%

Alternative approaches to target Myc for cancer treatment

Wang

Zhang

Yin

et al. 2021

Sig Transduct Target Ther

122

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The Myc proto-oncogene family consists of three members, C-MYC, MYCN, and MYCL, which encodes the transcription factor c-Myc (hereafter Myc), N-Myc, and L-Myc, respectively. Myc protein orchestrates diverse physiological processes, including cell proliferation, differentiation, survival, and apoptosis. Myc modulates about 15% of the global transcriptome, and its deregulation rewires the cellular signaling modules inside tumor cells, thereby acquiring selective advantages. The deregulation of Myc occurs in >70% of human cancers, and is related to poor prognosis; hence, hyperactivated Myc oncoprotein has been proposed as an ideal drug target for decades. Nevertheless, no specific drug is currently available to directly target Myc, mainly because of its “undruggable” properties: lack of enzymatic pocket for conventional small molecules to bind; inaccessibility for antibody due to the predominant nucleus localization of Myc. Although the topic of targeting Myc has actively been reviewed in the past decades, exciting new progresses in this field keep emerging. In this review, after a comprehensive summarization of valuable sources for potential druggable targets of Myc-driven cancer, we also peer into the promising future of utilizing macropinocytosis to deliver peptides like Omomyc or antibody agents to intracellular compartment for cancer treatment.

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Section: Alternative Methods To Target Mycmentioning

confidence: 99%

Alternative approaches to target Myc for cancer treatment

Wang

Zhang

Yin

et al. 2021

Sig Transduct Target Ther

122

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“…We present here a succinct summary of additional publications, which investigate and exploit the tremendous biomedical potential of bioportides in their various structural guises ( Figure 1D). Clearly, the broad scope of potential applications of cell permeable bioactive peptides, ranging from epigenetic modulation [87] to the blockade of Tolllike receptor (TLR) signalling, [88] suggests a very healthy future for such technologies.…”

Section: New Biology In New Directionsmentioning

confidence: 99%

“…Moreover, DPY30, significantly upregulated in some Burkitt's lymphoma samples, [89] enhances the methylation activity of SET1/MLL complexes by directly binding a relatively short 14 AA C-terminal segment of the ASH2L subunit. [87] A sychnologic bioportide (TAT-HA-ASH2L), combining the CPP Tat with an HA epitope tag and ASH2L 510-529 , binds DPY30 to block its interaction with ASH2L and significantly inhibit the growth of MLL-rearranged leukaemia and other haematological cancer cells. [87] A similar sychnologic strategy was employed to generate TIP1, [88] a bioportide combining penetratin with a sequence derived from the Toll/interleukin-1 receptor (TIR) domain-containing adaptor protein (SHCRVLLI).…”

Section: New Biology In New Directionsmentioning

confidence: 99%

“…[87] A sychnologic bioportide (TAT-HA-ASH2L), combining the CPP Tat with an HA epitope tag and ASH2L 510-529 , binds DPY30 to block its interaction with ASH2L and significantly inhibit the growth of MLL-rearranged leukaemia and other haematological cancer cells. [87] A similar sychnologic strategy was employed to generate TIP1, [88] a bioportide combining penetratin with a sequence derived from the Toll/interleukin-1 receptor (TIR) domain-containing adaptor protein (SHCRVLLI). TIP1 specifically binds the BB loop of the TLR4-TIR domain to inhibit multiple TLR signalling pathways and has therapeutic potential for the treatment of TLR-mediated autoimmune and inflammatory diseases.…”

Section: New Biology In New Directionsmentioning

confidence: 99%

See 1 more Smart Citation

A new biology of cell penetrating peptides

Howl

Jones

2020

Peptide Science

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As pharmacokinetic modifiers, cell penetrating peptides (CPPs) have proven utility for the delivery of otherwise impermeable cargoes into the discrete intracellular compartments of eukaryotic cells. Methods for the molecular optimisation of CPP sequences can significantly increase the performance of novel vectors matched to a specific delivery function. Moreover, the ‘information rich’ composition and inherent molecular flexibility of many CPPs can also facilitate their interaction with intracellular proteins and other cellular structures. This proteomimetic property of CPPs has been exploited in the design of bioportides, bioactive CPPs that regulate cellular functions often by binding relatively flat PPI interfaces to achieve a dominant negative action. This new biology of CPPs is rapidly gathering momentum through the design and synthesis of a bewildering variety of peptides that may be, in whole or part, linear, helical, cyclic and/or chimeric in nature. A particular emphasis of contemporary CPP‐centred drug discovery is the unmet medical need of cancer, though the biomedical scope of bioportide applications is impressively broad including cellular signalling and reprogramming. We are hopeful that one or more of the fascinating studies described herein will translate into the clinic to establish bioportide technologies as a viable option for drug discovery.

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“…To predict TFs regulating a query gene set, BART first apply Model-based Analysis of Regulation of Gene Expression (MARGE) (8) to derive a genomic cis-regulatory (enhancer) profile from the input gene set using a semi-supervised learning approach leveraging compendium ChIP-seq data for active enhancer histone mark H3K27ac, then generate a ranked list of TFs that have a highly correlated binding profile with the cis-regulatory profile. While proven to work for identifying functional TFs from many case studies (7,(9)(10)(11)(12), BART requires users to download large ChIP-seq data libraries that can be storage and memory-consuming, and sometimes runs slow primarily due to step-wise regression computation in MARGE.…”

Section: Introductionmentioning

confidence: 99%

BARTweb: a web server for transcription factor association analysis

Wang

Zhang

et al. 2020

Preprint

Self Cite

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Identifying active transcription factors (TFs) that bind to cis-regulatory regions in the genome to regulate differential gene expression is a key task in gene regulation research. TF binding profiles from numerous existing ChIP-seq data can be utilized for association analysis with query data for TF identification, as alternative to DNA sequence motif analysis. Here, we present BARTweb, an interactive webserver for identifying TFs whose genomic binding patterns associate with input genomic features, by leveraging over 13,000 public ChIP-seq datasets for human and mouse. Using an updated Binding Analysis for Regulation of Transcription (BART) algorithm, BARTweb can identify functional TFs that regulate a gene set, or have a binding profile correlated with a ChIP-seq profile or enriched in a genomic region set, without a priori information of the cell type. Compared with the original BART package, BARTweb substantially reduces the execution time of a typical job by two orders of magnitude. We also show that BARTweb outperforms other existing tools in identifying true TFs from collected experimental data. BARTweb is a useful webserver for performing functional analysis of gene regulation. BARTweb is freely available at http://bartweb.org.

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Specific inhibition of DPY30 activity by ASH2L-derived peptides suppresses blood cancer cell growth

Cited by 20 publications

References 65 publications

Alternative approaches to target Myc for cancer treatment

Alternative approaches to target Myc for cancer treatment

A new biology of cell penetrating peptides

BARTweb: a web server for transcription factor association analysis

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