PCAF-primed EZH2 acetylation regulates its stability and promotes lung adenocarcinoma progression

Wan, Junhu; Zhan, Jun; Li, Shuai; Ma, Ji; Xu, Weizhi; Liu, Chang; Xue, Xiaowei; Xie, Yuning; Fang, Wei‐Gang; Chin, Y. Eugene; Zhang, Hongquan

doi:10.1093/nar/gkv238

Cited by 111 publications

(103 citation statements)

References 43 publications

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“…As a known nutrition sensor and NAD-dependent deacetylase, Sirt1 has been extensively characterized for longevity regulation, and its activators have been shown to extend longevity and confer broad health benefits against aging-related diseases, including diabetes, heart disease, neurodegeneration and cancers [14, 41, 42]. Interestingly, EZH2 is deacetylated and negatively regulated by Sirt1 [39, 40], suggesting that E(z)/EZH2 may function downstream of Sirt1 to regulate nutrition-mediated longevity programming. Considering that addition of EPZ-6438 to the LP diet alleviated the LP-induced longevity decrease, it will be interesting to evaluate EPZ-6438's potential efficacy in alleviating LP-induced type II diabetes, cardiovascular disease and memory impairment [11, 18, 24].…”

Section: Discussionmentioning

confidence: 99%

“…This is significant, as diet and nutrition affects longevity across diverse single-celled, invertebrate and vertebrate animals [16]. Interestingly, EZH2 may be deacetylated and negatively regulated by Sirt1 [39, 40], an evolutionarily conserved nutrition sensor and well-characterized longevity gene [14, 41, 42], suggesting that E(z)/EZH2 may function downstream of Sirt1 to regulate nutrition-mediated longevity.…”

Section: Introductionmentioning

confidence: 99%

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Transgenerational programming of longevity through E(z)-mediated histone H3K27 trimethylation in Drosophila

Xia

Gerstin²,

Schones

et al. 2016

Aging

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Transgenerational effects on health and development of early-life nutrition have gained increased attention recently. However, the underlying mechanisms of transgenerational transmission are only starting to emerge, with epigenetics as perhaps the most important mechanism. We recently reported the first animal model to study transgenerational programming of longevity after early-life dietary manipulations, enabling investigations to identify underlying epigenetic mechanisms. We report here that post-eclosion dietary manipulation (PDM) with a low-protein (LP) diet upregulates the protein level of E(z), an H3K27 specific methyltransferase, leading to higher levels of H3K27 trimethylation (H3K27me3). This PDM-mediated change in H3K27me3 corresponded with a shortened longevity of F0 flies as well as their F2 offspring. Specific RNAi-mediated post-eclosion knockdown of E(z) or pharmacological inhibition of its enzymatic function with EPZ-6438 in the F0 parents improved longevity while rendering H3K27me3 low across generations. Importantly, addition of EPZ-6438 to the LP diet fully alleviated the longevity-reducing effect of the LP PDM, supporting the increased level of E(z)-dependent H3K27me3 as the primary cause and immediate early-life period as the critical time to program longevity through epigenetic regulation. These observations establish E(z)-mediated H3K27me3 as one epigenetic mechanism underlying nutritional programming of longevity and support the use of EPZ-6438 to extend lifespan.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Transgenerational programming of longevity through E(z)-mediated histone H3K27 trimethylation in Drosophila

Xia

Gerstin²,

Schones

et al. 2016

Aging

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“…The stable H1299 cells were crosslinked with 1% formaldehyde and subjected to chromatin immunoprecipitation (ChIP) assays as described before (27). The ChIP DNA complex were extracted and purified by DNA purification kit.…”

Section: Methodsmentioning

confidence: 99%

PCAF-mediated acetylation of transcriptional factor HOXB9 suppresses lung adenocarcinoma progression by targeting oncogenic protein JMJD6

Wan

Zhan

et al. 2016

Nucleic Acids Res

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HOXB9 is a homeobox domain-containing transcription factor, playing an important role in embryonic development and cancer progression. However, the precise post-translational modifications (PTMs) of HOXB9 and the corresponding roles are unclear. Here, we report that acetyltransferase p300/CBP-associated factor (PCAF) interacts with and acetylates HOXB9 both in vivo and in vitro. Conversely, the acetylation of HOXB9 can be reversed by deacetylase SIRT1. Furthermore, we found that HOXB9 is acetylated at lysine 27 (AcK27). Functionally, in contrast to the wild type HOXB9, AcK27-HOXB9 decreased its capacity in promoting lung cancer cell migration and tumor growth in mice. Mechanistically, AcK27-HOXB9 suppresses the transcription of its target gene Jumonji domain-containing protein 6 (JMJD6) by direct occupying the promoter of JMJD6 gene. For clinical relevance, elevated HOXB9 acetylation at K27 predicts a better prognosis in lung adenocarcinoma patients. Taken together, we identified the first PTM of HOXB9 by demonstrating that HOXB9 can be acetylated and AcK27-HOXB9 counteracts the role of the wild-type HOXB9 in regulating lung adenocarcinoma progression.

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“…For PDCD1LG2 and PKD2, there was no publication suggesting their roles in NSCLC. In contrast, the EZH (enhancer of zeste homolog) family appears to play an important role in NSCLC [22][23][24][25][26]. Thus, we explored if EZH1 is a target of miR-17-5p and there was a good alignment between 3 0 -UTR of EZH1 mRNA and miR-17-5p seed sequence (Figure 4(A)).…”

Section: Ezh1 Is a Target Of Mir-17-5pmentioning

confidence: 99%

miR-17-5p down-regulation contributes to erlotinib resistance in non-small cell lung cancer cells

Zhang

Lin

Wang

et al. 2016

Journal of Drug Targeting

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Non-small cell lung cancer (NSCLC) is the major cause of lung cancer-related deaths. Erlotinib is an effective drug for NSCLC patients, but its effect in advanced NSCLC is compromised because of the drug resistance. The mechanism of erlotinib resistance in NSCLC is largely unknown. In the current study, we found that erlotinib treatment down-regulated miR-17-5p level in A549 cells and miR-17-5p was lower in acquired erlotinib-resistant A549 cells (A549-ER) compared with erlotinib-sensitive A549 cells. Consistently, miR-17-5p was down-regulated in the tumor tissues and the plasma of erlotinib-resistant NSCLC patients in comparison to those who are sensitive to erlotinib. Moreover, miR-17-5p mimic increased the sensitivity of A549 and A549-ER to erlotinib. In contrast, miR-17-5p inhibitor decreased the cell death of A549 and A549-ER induced by erlotinib. In addition, we also demonstrated that miR-17-5p could inhibit the mRNA and protein levels of enhancer of zeste homolog (EZH) 1, a member of the EZH family that contributes to drug resistance in several types of cancer. The luciferase assay of 3 0 -untranslated region (UTR) demonstrates that EZH1 is a direct target of miR-17-5p and EZH1 RNAi recapitulates the effect of miR-17-5p overexpression on erlotinib resistance. Further, mutation in seed sequence of miR-17-5p could totally abolish the sensitization of A549-ER to erlotinib induced by miR-17-5p overexpression. Our results indicate that miR-17-5p down-regulation contributes to erlotinib resistance of NSCLC by modulating its target genes such as EZH1 and plasma miR-17-5p might be a potential biomarker of erlotinib response in NSCLC patients. ARTICLE HISTORY

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PCAF-primed EZH2 acetylation regulates its stability and promotes lung adenocarcinoma progression

Cited by 111 publications

References 43 publications

Transgenerational programming of longevity through E(z)-mediated histone H3K27 trimethylation in Drosophila

Transgenerational programming of longevity through E(z)-mediated histone H3K27 trimethylation in Drosophila

PCAF-mediated acetylation of transcriptional factor HOXB9 suppresses lung adenocarcinoma progression by targeting oncogenic protein JMJD6

miR-17-5p down-regulation contributes to erlotinib resistance in non-small cell lung cancer cells

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