Selective p300 inhibitor C646 inhibited HPV E6-E7 genes, altered glucose metabolism and induced apoptosis in cervical cancer cells

He, Hongbin; Lai, Yongwei; Hao, Yunpeng; Liu, Yupeng; Zhang, Zijiang; Xiang, Liu; Guo, Chenhong; Zhang, Mengmeng; Zhou, Hao; Wang, Nan; Luo, Xue‐Gang; Huo, Lihong; Ma, Wenjian; Zhang, Tongcun

doi:10.1016/j.ejphar.2017.06.005

Cited by 24 publications

(17 citation statements)

References 33 publications

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“…In view of the proapoptotic effect of C646 in tumor cells 23,24 , we examined the effect of C646 on pAVICs after calcification medium treatment. In contrast to tumor cells, pAVICs treated with 10 μM C646 exhibited an inhibition of apoptosis induced by high-calcium/high-phosphate conditions (Fig.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of acetylation of histones 3 and 4 attenuates aortic valve calcification

Lü

Deng

et al. 2019

Exp Mol Med

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Aortic valve calcification develops in patients with chronic kidney disease who have calcium and phosphate metabolic disorders and poor prognoses. There is no effective treatment except valve replacement. However, metabolic disorders put patients at high risk for surgery. Increased acetylation of histones 3 and 4 is present in interstitial cells from human calcific aortic valves, but whether it is involved in aortic valve calcification has not been studied. In this study, we found that treating cultured porcine aortic valve interstitial cells with a high-calcium/high-phosphate medium induced calcium deposition, apoptosis, and expression of osteogenic marker genes, producing a phenotype resembling valve calcification in vivo. These phenotypic changes were attenuated by the histone acetyltransferase inhibitor C646. C646 treatment increased the levels of class I histone deacetylase members and decreased the acetylation of histones 3 and 4 induced by the high-calcium/high-phosphate treatment. Conversely, the histone deacetylase inhibitor suberoylanilide hydroxamic acid promoted valve interstitial cell calcification. In a mouse model of aortic valve calcification induced by adenine and vitamin D treatment, the levels of acetylated histones 3 and 4 were increased in the calcified aortic valves. Treatment of the models with C646 attenuated aortic valve calcification by restoring the levels of acetylated histones 3 and 4. These observations suggest that increased acetylation of histones 3 and 4 is part of the pathogenesis of aortic valve calcification associated with calcium and phosphate metabolic disorders. Targeting acetylated histones 3 and 4 may be a potential therapy for inoperable aortic valve calcification in chronic kidney disease patients.

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Section: Resultsmentioning

confidence: 99%

Inhibition of acetylation of histones 3 and 4 attenuates aortic valve calcification

Lü

Deng

et al. 2019

Exp Mol Med

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“…Just recently the metabolism-modulatory functions of EP300 have been described in more detail. Among others, these studies revealed EP300's role in promoting genes involved in glycolysis and demonstrated that EP300 inhibition leads to a disruption of glucose metabolism 22,23 . Consequently, we hypothesized that EP300 upregulation is associated with a glycolysis-dominant tumor metabolism, whereas EP300 downregulation correlates with an OXPHOS-dominant tumor metabolism.…”

Section: Resultsmentioning

confidence: 99%

“…Recent studies have shown that EP300 is a promoter of glycolysis and inhibition of EP300 leads to inhibition of glucose metabolism 22,23 . Tumor cell glucose metabolism, however, is known to exert inhibitory effects on T cell proliferation, tumor infiltration by T cells and T cell guided anti-tumor immune response 48 .…”

Section: Discussionmentioning

confidence: 99%

In silico analysis reveals EP300 as a panCancer inhibitor of anti-tumor immune response via metabolic modulation

Krupar

Watermann

Idel

et al. 2020

Sci Rep

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“…Interestingly, a previous study showed that overexpression of cyclooxygenase (COX-2) gene was the result of the recruitment of p300 to its promoter region via the overexpression of HPV-16 E6 protein in CaSki cells as well as the exogenous expression of HPV-16 E6 in HPV-negative C-33A cells 52 . Recently, p300 inhibitors such as C646 have been shown to be good candidates as anti-cervical cancer drugs, demonstrating the importance of p300 not only in the regulation of host genes but also of HPV viral genes 53 .…”

Section: Discussionmentioning

confidence: 99%

Long non-coding RNA FAM83H-AS1 is regulated by human papillomavirus 16 E6 independently of p53 in cervical cancer cells

Barr

Hayes

Brownmiller

et al. 2019

Sci Rep

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High-risk human papillomavirus (HPV) infection is one of the first events in the process of carcinogenesis in cervical and head and neck cancers. The expression of the viral oncoproteins E6 and E7 are essential in this process by inactivating the tumor suppressor proteins p53 and Rb, respectively, in addition to their interactions with other host proteins. Non-coding RNAs, such as long non-coding RNAs (lncRNAs) have been found to be dysregulated in several cancers, suggesting an important role in tumorigenesis. In order to identify host lncRNAs affected by HPV infection, we expressed the high-risk HPV-16 E6 oncoprotein in primary human keratinocytes and measured the global lncRNA expression profile by high-throughput sequencing (RNA-seq). We found several host lncRNAs differentially expressed by E6 including GAS5, H19, and FAM83H-AS1. Interestingly, FAM83H-AS1 was found overexpressed in HPV-16 positive cervical cancer cell lines in an HPV-16 E6-dependent manner but independently of p53 regulation. Furthermore, FAM83H-AS1 was found to be regulated through the E6-p300 pathway. Knockdown of FAM83H-AS1 by siRNAs decreased cellular proliferation, migration and increased apoptosis. FAM83H-AS1 was also found to be altered in human cervical cancer tissues and high expression of this lncRNA was associated with worse overall survival, suggesting an important role in cervical carcinogenesis.

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Selective p300 inhibitor C646 inhibited HPV E6-E7 genes, altered glucose metabolism and induced apoptosis in cervical cancer cells

Cited by 24 publications

References 33 publications

Inhibition of acetylation of histones 3 and 4 attenuates aortic valve calcification

Inhibition of acetylation of histones 3 and 4 attenuates aortic valve calcification

In silico analysis reveals EP300 as a panCancer inhibitor of anti-tumor immune response via metabolic modulation

Long non-coding RNA FAM83H-AS1 is regulated by human papillomavirus 16 E6 independently of p53 in cervical cancer cells

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