Unexpected implications of STAT3 acetylation revealed by genetic encoding of acetyl-lysine

Belo, Yael; Mielko, Zachery; Nudelman, Hila; Afek, Ariel; Ben-David, Oshrit; Shahar, Amit; Zarivach, Raz; Gordân, Raluca; Arbely, Eyal

doi:10.1016/j.bbagen.2019.05.019

Cited by 39 publications

(26 citation statements)

References 46 publications

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“…Although the underlying mechanism via which chidamide restrains the expression of STAT3 requires further study, the present results also demonstrated that expression level of the anti-apoptotic Bcl-2 protein, a downstream target of STAT3 ( 38 ), was attenuated by chidamide treatment, which decreased the expression level STAT3 and its phosphorylation activities in DLBCL cells. This was consistent with the finding that phosphorylation is a pattern of activity regulation for STAT3 ( 39 ). In future studies, deletion of Bcl-2 and STAT3 using small interfering RNA will be performed to further reveal the mechanism of the anticancer effects of chidamide.…”

Section: Discussionsupporting

confidence: 92%

Chidamide induces apoptosis in DLBCL cells by suppressing the HDACs/STAT3/Bcl‑2 pathway

et al. 2021

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Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous malignant tumor type, and epigenetic modifications such as acetylation or deacetylation serve vital roles in its development. Chidamide, a novel histone deacetylase inhibitor, exerts an anticancer effect against various types of cancer. The present study aimed to evaluate the cellular effect of chidamide on a number of DLBCL cell lines and to investigate its underlying mechanism. The results demonstrated that chidamide induced the death of these cells in a concentration-(0-30 µmol/l) and time-dependent (24-72 h) manner, as determined using the Cell Counting Kit-8 cell viability assay. Moreover, chidamide promoted cellular apoptosis, which was identified via flow cytometry and western blot analysis, with an increase in cleaved caspase-3 expression and a decrease in Bcl-2 expression. Chidamide treatment also decreased the expression level of STAT3 and its phosphorylation, which was accompanied by the downregulation of a class-I histone deacetylase (HDAC) inhibitor, chidamide. Collectively, these data suggested that chidamide can be a potent therapeutic agent to treat DLBCL by inducing the apoptotic death of DLBCL cells by inhibiting the HDACs/STAT3/Bcl-2 pathway.

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Section: Discussionsupporting

confidence: 92%

Chidamide induces apoptosis in DLBCL cells by suppressing the HDACs/STAT3/Bcl‑2 pathway

et al. 2021

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“…For SaMBA experiments, full-length human proteins Ets1, Elk1, Gabpa, Runx1, E2f1, Six6, Ap2a, Gata1, Myc (c-Myc), Max, Mad (Mad1), human Egr1 residues 335–423, human RelA residues 20–290, human GR residues 418–517, human Stat3 residues 128–715, and full-length S. cerevisiae Cbf1 were expressed and purified as described previously 21 , 57 – 60 . Full-length human p53, TBP, CTCF, Creb1, Crem, and Atf1 were obtained commercially ( Supplementary Methods ).…”

Section: Methodsmentioning

confidence: 99%

DNA mismatches reveal conformational penalties in protein–DNA recognition

Afek

Shi

Sahay

et al. 2020

Nature

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101

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SUMMARY PARAGRAPH Transcription factors (TF) recognize specific genomic sequences to regulate complex gene expression programs. Although it is well established that TFs bind specific DNA sequences using a combination of base readout and shape recognition, some fundamental aspects of protein-DNA binding remain poorly understood 1 , 2 . Many DNA-binding proteins induce changes in the DNA structure outside the intrinsic B-DNA envelope. However, how the energetic cost associated with distorting DNA contributes to recognition has proven difficult to study because the distorted DNA exists in low-abundance in the unbound ensemble 3 – 9 . Here, we use a novel high-throughput assay called SaMBA ( Sa turation M ismatch- B inding A ssay) to investigate the role of DNA conformational penalties in TF-DNA recognition. In SaMBA, mismatches are introduced to pre-induce DNA structural distortions much larger than those induced by changes in Watson-Crick sequence. Strikingly, approximately 10% of mismatches increased TF binding, and at least one mismatch was found that increased the binding affinity for each of 22 examined TFs. Mismatches also converted non-specific sites into high-affinity sites, and high-affinity sites into super-sites stronger than any known canonical binding site. Determination of high-resolution X-ray structures, combined with NMR measurements and structural analyses revealed that many of the mismatches that increase binding induce distortions similar to those induced by protein binding, thus pre-paying some of the energetic cost to deform the DNA. Our work indicates that conformational penalties are a major determinant of protein-DNA recognition, and reveals mechanisms by which mismatches can recruit TFs and thus modulate replication and repair activities in the cell 10 , 11 .

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“…The structure file of the STAT3 protein (PDB ID:6QHD) was extracted from the Research Collaboratory for Structural Bioinformatics Protein Data Bank (http://www.rcsb.org/). 35,36 The protein is an X‐ray crystal homodimer structure bound to the DNA, at 2.85 Å resolution 37 . All heteroatom, including double‐stranded DNA and crystallographic water were removed, and chain A was kept as a STAT3 monomer.…”

Section: Methodsmentioning

confidence: 99%

Resveratrol suppresses the growth and metastatic potential of cervical cancer by inhibiting STAT3^Tyr705 phosphorylation

Sun

Zeng

et al. 2020

Cancer Medicine

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Unexpected implications of STAT3 acetylation revealed by genetic encoding of acetyl-lysine

Cited by 39 publications

References 46 publications

Chidamide induces apoptosis in DLBCL cells by suppressing the HDACs/STAT3/Bcl‑2 pathway

Chidamide induces apoptosis in DLBCL cells by suppressing the HDACs/STAT3/Bcl‑2 pathway

DNA mismatches reveal conformational penalties in protein–DNA recognition

Resveratrol suppresses the growth and metastatic potential of cervical cancer by inhibiting STAT3^Tyr705 phosphorylation

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Unexpected implications of STAT3 acetylation revealed by genetic encoding of acetyl-lysine

Cited by 39 publications

References 46 publications

Chidamide induces apoptosis in DLBCL cells by suppressing the HDACs/STAT3/Bcl‑2 pathway

Chidamide induces apoptosis in DLBCL cells by suppressing the HDACs/STAT3/Bcl‑2 pathway

DNA mismatches reveal conformational penalties in protein–DNA recognition

Resveratrol suppresses the growth and metastatic potential of cervical cancer by inhibiting STAT3Tyr705 phosphorylation

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Product

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Resveratrol suppresses the growth and metastatic potential of cervical cancer by inhibiting STAT3^Tyr705 phosphorylation