<scp>PCAF</scp>‐mediated acetylation of <scp>ISX</scp> recruits <scp>BRD</scp>4 to promote epithelial‐mesenchymal transition

Wang, Li Ting; Liu, Kwei Yan; Jeng, W.Y.; Chiang, Cheng Ming; Chai, Chee‐Yin; Chiou, Shyh Shin; Huang, Ming-Shyan; Yokoyama, Kazunari K.; Wang, Shen Nien; Huang, Shau Ku; Hsu, Shih-Hsien

doi:10.15252/embr.201948795

Cited by 35 publications

(37 citation statements)

References 51 publications

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“…Among HDACs, SIRT1, 2, and 4 were mainly located in mitochondria and cytoplasm, and they were closely related to metabolic process and oxidative stress during cancer development ( Min et al, 2018 ; Watanabe et al, 2018 ; Lee et al, 2018 ). Besides histones, increasing numbers of non-histone proteins were identified as substrates of sirutins, which included several metabolic enzymes identified in this study ( Wang L.T. et al, 2020 ; Xu et al, 2014 ).…”

Section: Discussionmentioning

confidence: 84%

Lysine Acetylome Study of Human Hepatocellular Carcinoma Tissues for Biomarkers and Therapeutic Targets Discovery

Zhao

Zhang

et al. 2020

Front. Genet.

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Lysine acetylation is a vital post-translational modification (PTM) of proteins, which plays an important role in cancer development. In healthy human liver tissues, multiple non-histone proteins were identified with acetylation modification, however, the role of acetylated proteins in hepatocellular carcinoma (HCC) development remains largely unknown. Here we performed a quantitative acetylome study of tumor and normal liver tissues from HCC patients. Overall, 598 lysine acetylation sites in 325 proteins were quantified, and almost 59% of their acetylation levels were significantly changed. The differentially acetylated proteins mainly consisted of non-histone proteins located in mitochondria and cytoplasm, which accounted for 42% and 24%, respectively. Bioinformatics analysis showed that differentially acetylated proteins were enriched in metabolism, oxidative stress, and signal transduction processes. In tumor tissues, 278 lysine sites in 189 proteins showed decreased acetylation levels, which occupied 98% of differentially acetylated proteins. Moreover, we collected twenty pairs of tumor and normal liver tissues from HCC male patients, and found that expression levels of SIRT1 (p = 0.002), SIRT2 (p = 0.01), and SIRT4 (p = 0.045) were significantly up-regulated in tumor tissues. Over-expression of possibly accounted for the widespread deacetylation of non-histone proteins identified in HCC tumor tissues, which could serve as promising predictors of HCC. Taken together, our work illustrates abundant differentially acetylated proteins in HCC tumor tissues, and offered insights into the role of lysine acetylation in HCC development. It provided potential biomarker and drug target candidates for clinical HCC diagnosis and treatment.

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Section: Discussionmentioning

confidence: 84%

Lysine Acetylome Study of Human Hepatocellular Carcinoma Tissues for Biomarkers and Therapeutic Targets Discovery

Zhao

Zhang

et al. 2020

Front. Genet.

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“…In addition, p300/CBP-associated factor (PCAF)-dependent acetylation of the transcription factor intestine-specific homeobox (ISX) promotes its interaction with BRD4 and translocation of the resulting complex into the nucleus. This complex binds to promoters of EMT genes, where acetylation of histone three at lysine 9, 14, and 18 thus initiates transcriptional activation; these findings indicate that the p300/CBP-ISX-BRD4 axis mediates EMT and regulates tumor initiation and metastasis (Wang L.-T. et al, 2020).…”

Section: Epithelial-mesenchymal Transition and Histone Modification Amentioning

confidence: 93%

Tackle Epithelial-Mesenchymal Transition With Epigenetic Drugs in Cancer

Dong

Qiu

2020

Front. Pharmacol.

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Epithelial-mesenchymal Transition (EMT) is a de-differentiation process in which epithelial cells lose their epithelial properties to acquire mesenchymal features. EMT is essential for embryogenesis and wound healing but is aberrantly activated in pathological conditions like fibrosis and cancer. Tumor-associated EMT contributes to cancer cell initiation, invasion, metastasis, drug resistance and recurrence. This dynamic and reversible event is governed by EMT-transcription factors (EMT-TFs) with epigenetic complexes. In this review, we discuss recent advances regarding the mechanisms that modulate EMT in the context of epigenetic regulation, with emphasis on epigenetic drugs, such as DNA demethylating reagents, inhibitors of histone modifiers and non-coding RNA medication. Therapeutic contributions that improve epigenetic regulation of EMT will translate the clinical manifestation as treating cancer progression more efficiently.

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“…GCN5 inhibition prevents EMT, migration and invasion of breast cancer cells. Another acetyltransferase family member, PCAF promotes EMT and cancer metastasis [ 86 ]. The p300 acetylase has been shown to interact with a complex comprised of the Disruptor of telomeric silencing 1-like (DOT1L) histone lysine methyltransferase and c-Myc , activating EMT regulators in breast cancer, and serving as a potential oncogene responsible for the formation of an aggressive phenotype and transformation of cancer stem cells (CSCs) [ 87 ].…”

Section: Cancer-type Specific Histone Modifications Regulating Tummentioning

confidence: 99%

Prominent Role of Histone Modifications in the Regulation of Tumor Metastasis

Markouli

Strepkos

Basdra

et al. 2021

IJMS

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Tumor aggressiveness and progression is highly dependent on the process of metastasis, regulated by the coordinated interplay of genetic and epigenetic mechanisms. Metastasis involves several steps of epithelial to mesenchymal transition (EMT), anoikis resistance, intra- and extravasation, and new tissue colonization. EMT is considered as the most critical process allowing cancer cells to switch their epithelial characteristics and acquire mesenchymal properties. Emerging evidence demonstrates that epigenetics mechanisms, DNA methylation, histone modifications, and non-coding RNAs participate in the widespread changes of gene expression that characterize the metastatic phenotype. At the chromatin level, active and repressive histone post-translational modifications (PTM) in association with pleiotropic transcription factors regulate pivotal genes involved in the initiation of the EMT process as well as in intravasation and anoikis resistance, playing a central role in the progression of tumors. Herein, we discuss the main epigenetic mechanisms associated with the different steps of metastatic process, focusing in particular on the prominent role of histone modifications and the modifying enzymes that mediate transcriptional regulation of genes associated with tumor progression. We further discuss the development of novel treatment strategies targeting the reversibility of histone modifications and highlight their importance in the future of cancer therapy.

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PCAF‐mediated acetylation of ISX recruits BRD4 to promote epithelial‐mesenchymal transition

Cited by 35 publications

References 51 publications

Lysine Acetylome Study of Human Hepatocellular Carcinoma Tissues for Biomarkers and Therapeutic Targets Discovery

Lysine Acetylome Study of Human Hepatocellular Carcinoma Tissues for Biomarkers and Therapeutic Targets Discovery

Tackle Epithelial-Mesenchymal Transition With Epigenetic Drugs in Cancer

Prominent Role of Histone Modifications in the Regulation of Tumor Metastasis

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