&lt;p&gt;Histone deacetylase 6 is overexpressed and promotes tumor growth of colon cancer through regulation of the MAPK/ERK signal pathway&lt;/p&gt;

Zhang, Shi-Lan; Zhu, Hongyi; Zhou, Boting; Chu, Yi-Min; Huo, Jirong; Tan, Yuyong; Liu, Deliang

doi:10.2147/ott.s194986

Cited by 33 publications

(38 citation statements)

References 39 publications

(33 reference statements)

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“…Additionally, our findings also revealed that E2F7 promoted MAPK stability to enhance cell proliferation, invasion, and migration in colon cancer. Similarly, a prior study elucidated the association of the MAPK signaling pathway with colon cancer growth in vivo ( 27 ). Notably, MAPK has been found to promote colon cancer tumor stem cell activity ( 15 ).…”

Section: Discussionmentioning

confidence: 98%

E2F7 Transcriptionally Inhibits MicroRNA-199b Expression to Promote USP47, Thereby Enhancing Colon Cancer Tumor Stem Cell Activity and Promoting the Occurrence of Colon Cancer

et al. 2021

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microRNAs (miRNAs) can modulate the expression level of genes in a post-transcription manner, which are closely related to growth and metastasis of colon cancer. Herein, we aimed to explore how miR-199b influences colon cancer and to characterize its underlying molecular mechanism associating with E2F transcription factor 7 (E2F7). Assays of RT-qPCR, Western blot, and immunohistochemistry were utilized to detect the expression of E2F7 in the tissue samples collected from 30 patients diagnosed with colon cancer. Flow analysis was utilized to detect the ratio of ALDH1+ and CD133+ colon cancer stem cells. The interaction between E2F7, miR-199b, USP47, and MAPK was identified by ChIP-Seq analysis, luciferase reporter, RNA pull-down, co-immunoprecipitation, as well as glutathione-S-transferase (GST) pull-down experiments. Based on the gain- and loss-of-function approaches, the cellular functions of colon cancer cells by the E2F7-regulated miR-199b/USP47/MAPK axis were assessed. It was identified that E2F7 are expressed highly in the collected colon cancer tissues. E2F7 silencing reduced the production of ALDH1+ and CD133+ colon cancer stem cells and antagonized the effects of 5-fluorouracil (5-FU) treatment. Besides, the silencing of E2F7 was observed to suppress the oxidative stress, proliferation, migration, as well as invasion of ALDH1+ cells in vitro and tumorigenesis of colon cancer cells in vivo. Our findings reveal the pro-oncogenic effect of E2F7 on colon cancer development, highlighting E2F7 as a novel target for therapeutic strategy for colon cancer.

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Section: Discussionmentioning

confidence: 98%

E2F7 Transcriptionally Inhibits MicroRNA-199b Expression to Promote USP47, Thereby Enhancing Colon Cancer Tumor Stem Cell Activity and Promoting the Occurrence of Colon Cancer

et al. 2021

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“…However, donepezil failed to increase the p-AKT/AKT ratio in the hippocampus. Previous studies have also indicated that p-AKT is decreased upon the knockdown of HDAC6 [ 28 ], which implies that AKT is associated with the regulation of HDAC6. However, further investigation is needed to confirm the relationship between HDAC6 nuclear translocation and p-AKT.…”

Section: Discussionmentioning

confidence: 92%

Donepezil attenuates vascular dementia in rats through increasing BDNF induced by reducing HDAC6 nuclear translocation

et al. 2020

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Vascular dementia (VD) is the second most common dementia disease after Alzheimer’s diseases (AD) in the world. Donepezil is used to treat mild to moderate AD, and it has been shown to treat cognitive impairment and memory deficits caused by VD. However, the action mechanism of donepezil against VD has not been clarified. In this study, a bilateral common carotid artery occlusion (BCCAO) model was established in rats to simulate the pathology of VD. Two weeks after the surgery, the rats were administered donepezil (10 mg · kg −1 · d −1 , ig) for 3 weeks, and then subjected to behavioral tests. We showed that donepezil treatment significantly improved the performance of BCCAO rats in Morris Water Mazes test and Step-down test. Furthermore, we showed that donepezil treatment significantly attenuated neurodegeneration and restored the synapse dendritic spines density in cortex and hippocampus. We revealed that donepezil treatment significantly increased BDNF expression in cortex and hippocampus. Interestingly, donepezil treatment significantly decreased nuclear translocation of HDAC6 and the binding between HDAC6 and BDNF promoter IV in cortex, but not in the hippocampus. The attenuated neurodegeneration by donepezil in cortex and hippocampus might due to the reduced ROS levels and increased phosphorylation of AMPK, whereas increased phosphorylation of AKT was only detected in cortex. In conclusion, our results demonstrate that donepezil attenuates neurodegeneration in cortex and hippocampus via increasing BDNF expression; the regulation of donepezil on HDAC6 occurred in cortex, but not in the hippocampus. This study further clarifies the pharmacological mechanism of donepezil, while also emphasizes the promising epigenetic regulation of HDAC6.

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“…HDAC6 overexpression promotes colorectal tumor growth and selective inhibition synergistically induces CRC cell death (39). Recently we described a selective hydroxamate-based small-molecule HDAC6 inhibitor (C1A), with good pharmacokinetics and ability to modulate autophagy in vitro and in vivo in different cancer subtypes including CRC cells (12).…”

Section: Resultsmentioning

confidence: 99%

“…The overexpression of HDAC6 was found to be associated with larger tumor sizes in CRC indicating its key role in CRC progression (6,39 Extraction, isolation and purification of histones. Cancer cell lines were harvested at 80% confluence through trypsination.…”

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confidence: 99%

Novel nuclear role of HDAC6 in prognosis and therapeutic target for colorectal cancer

Hontecillas-Prieto

Kaliszczak

et al. 2020

Preprint

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Histone deacetylase 6 (HDAC6) inhibition is a potential treatment of a wide range of cancer types via the acetylation of diverse proteins in the cytoplasm. However, the regulation of histone acetylation and the maintenance of higher-order chromatin structure remains unidentified. Here, we investigated the effect of selective inhibition of HDAC6 by histone acetylation, chromatin relaxation assays, co-immunoprecipitation, acetylome peptide array and in vivo RNA microarray. Our data shows that nuclear HDAC6 physically interacts with the Histone 4 lysine 12 residue, and that HDAC6 inhibition increases acetylation specifically at this residue in several cancer types. Inhibition induces major chromatin structure modulation, but has no equivalent effect on knockout HDAC6-/- MEF cells. We identified several novel HDAC6-deacetylated substrates and high expression of HDAC6 in colorectal cancer (CRC) tissue association with reduced levels of H4K12ac and independent of the key CRC driver mutations, but positively associated with EGFR expression. Furthermore, in vivo HDAC6 inhibition induces significant tumor regression in a CRC xenograft mice model with significant changes in the expression of functional nuclear genes. We also demonstrated that a DNA damaging agent in combination with selective HDAC6 inhibition is effective and acts synergistically, inducing chromatin relaxation and increased cell death in CRC cells. CRC tissues (Normal versus tumor; n=58 matched pairs) together with TCGA data analysis of 467 CRC patients showed that high HDAC6 expression is associated with metastasis, overall and disease-free survival, and is an independent risk factor of CRC stage progression. Our findings designate a new role for nuclear HDAC6 both in cancer prognosis and as a new therapeutic target for CRC and other types of cancer.

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<p>Histone deacetylase 6 is overexpressed and promotes tumor growth of colon cancer through regulation of the MAPK/ERK signal pathway</p>

Cited by 33 publications

References 39 publications

E2F7 Transcriptionally Inhibits MicroRNA-199b Expression to Promote USP47, Thereby Enhancing Colon Cancer Tumor Stem Cell Activity and Promoting the Occurrence of Colon Cancer

E2F7 Transcriptionally Inhibits MicroRNA-199b Expression to Promote USP47, Thereby Enhancing Colon Cancer Tumor Stem Cell Activity and Promoting the Occurrence of Colon Cancer

Donepezil attenuates vascular dementia in rats through increasing BDNF induced by reducing HDAC6 nuclear translocation

Novel nuclear role of HDAC6 in prognosis and therapeutic target for colorectal cancer

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