Promoter Hypomethylation and miR-145-5p Downregulation- Mediated HDAC11 Overexpression Promotes Sorafenib Resistance and Metastasis of Hepatocellular Carcinoma Cells

Wang, Wenlong; Ding, Bo; Lou, Weiyang; Lin, Sensen

doi:10.3389/fcell.2020.00724

Cited by 30 publications

(23 citation statements)

References 30 publications

(33 reference statements)

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“…Accordingly, in human HCC, we observed that a low SNAI1 promoter methylation is a risk factor for tumor recurrence and metastasis. These results underscore demethylation in early stages of liver cancer as a risk factor for tumor progression [ 53 , 54 , 55 ]. They also provide critical information that may help to develop a strategy for the treatment of HCC patients according to the epigenetic pattern of genes associated with the TGFβ pathway.…”

Section: Discussionmentioning

confidence: 83%

DNA Methylation of TGFβ Target Genes: Epigenetic Control of TGFβ Functional Duality in Liver Cancer

Bévant

Desoteux

Wahab

et al. 2021

Cells

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Transforming growth factor beta (TGFβ) plays a key role in liver carcinogenesis. However, its action is complex, since TGFβ exhibits tumor-suppressive or oncogenic properties, depending on the tumor stage. At an early stage TGFβ exhibits cytostatic features, but at a later stage it promotes cell growth and metastasis, as a potent inducer of epithelial to mesenchymal transition (EMT). Here, we evaluated DNA methylation as a possible molecular mechanism switching TGFβ activity toward tumor progression in hepatocellular carcinoma (HCC). We report that decitabine, a demethylating agent already used in the clinic for the treatment of several cancers, greatly impairs the transcriptional response of SNU449 HCC cells to TGFβ. Importantly, decitabine was shown to induce the expression of EMT-related transcription factors (e.g., SNAI1/2, ZEB1/2). We also report that the promoter of SNAI1 was hypomethylated in poor-prognosis human HCC, i.e., associated with high grade, high AFP level, metastasis and recurrence. Altogether, the data highlight an epigenetic control of several effectors of the TGFβ pathway in human HCC possibly involved in switching its action toward EMT and tumor progression. Thus, we conclude that epidrugs should be carefully evaluated for the treatment of HCC, as they may activate tumor promoting pathways.

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Section: Discussionmentioning

confidence: 83%

DNA Methylation of TGFβ Target Genes: Epigenetic Control of TGFβ Functional Duality in Liver Cancer

Bévant

Desoteux

Wahab

et al. 2021

Cells

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“…Due to the observed anticorrelation of HDAC11 expression in proliferating cells and its shared induction in cell cycle arrested and differentiated cells, HDAC11 could be a candidate to be dysregulated in human cancers. HDAC11 is overexpressed in numerous cancers, including hepatocellular [92,99,126,127], prostate [100], ovarian [128], pituitary [129], pancreatic [130], myeloma [131,132], and lymphoma [133]. Interestingly, HDAC11 inhibition has demonstrated beneficial effects in neuroblastoma cells [134] and Hodgkin lymphoma [135].…”

Section: Cancermentioning

confidence: 99%

“…Regarding other epigenetic mechanisms of regulation, HDAC11 contains a CpG island (CpGi) in its promoter, overlapping its transcriptional start site. Although there are very limited data about its CpGi DNA methylation levels, HDAC11 seems to be completely demethylated in skeletal muscle cells [70], and its methylation levels might be dysregulated in some pathologies [91,92].…”

Section: Overview Of the Hdac11 Expression Profiles And Gene Regulationmentioning

confidence: 99%

HDAC11: a multifaceted histone deacetylase with proficient fatty deacylase activity and its roles in physiological processes

Núñez‐Álvarez

Suelves

2021

The FEBS Journal

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The histone deacetylases (HDACs) family of enzymes possess deacylase activity for histone and nonhistone proteins; HDAC11 is the latest discovered HDAC and the only member of class IV. Besides its shared HDAC family catalytical activity, recent studies underline HDAC11 as a multifaceted enzyme with a very efficient long-chain fatty acid deacylase activity, which has open a whole new field of action for this protein. Here, we summarize the importance of HDAC11 in a vast array of cellular pathways, which has been recently highlighted by discoveries about its subcellular localization, biochemical features, and its regulation by microRNAs and long noncoding RNAs, as well as its new targets and interactors. Additionally, we discuss the recent work showing the consequences of HDAC11 dysregulation in brain, skeletal muscle, and adipose tissue, and during regeneration in response to kidney, skeletal muscle, and vascular injuries, underscoring HDAC11 as an emerging hub protein with physiological functions that are much more extensive than previously thought, and with important implications in human diseases.

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“…Seventh, miR-374b inhibits the progression of HCC and re-sensitizes HCC cells to sorafenib through antagonizing the PKM2-related glycolysis pathways (28). Eighth, downregulation of miR-145-5p and promoter hypomethylation mediated HDAC11 overexpression affects the metabolism of HCC cells and tissues, and facilitates the metastasis of HCC cells and their resistance to sorafenib (33). Ninth, miR-3609 retards the sorafenib clearance in HCC cells through regulating EPAS-1 and inhibiting activation of the gestation hormone X receptor pathway (38).…”

Section: Other Pathwaysmentioning

confidence: 99%

The Role of Non-Coding RNAs in the Sorafenib Resistance of Hepatocellular Carcinoma

Zhu

Shen

et al. 2021

Front. Oncol.

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Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death. Sorafenib is approved by the U.S. Food and Drug Administration to be a first-line chemotherapy agent for patients with advanced HCC. A portion of advanced HCC patients can benefit from the treatment with sorafenib, but many patients ultimately develop sorafenib resistance, leading to a poor prognosis. The molecular mechanisms of sorafenib resistance are sophisticated and indefinite. Notably, non-coding RNAs (ncRNAs), which include long ncRNAs (lncRNAs), microRNAs (miRNAs) and circular RNAs (circRNAs), are critically participated in the occurrence and progression of tumors. Moreover, growing evidence has suggested that ncRNAs are crucial regulators in the development of resistance to sorafenib. Herein, we integrally and systematically summarized the molecular mechanisms and vital role of ncRNAs impact sorafenib resistance of HCC, and ultimately explored the potential clinical administrations of ncRNAs as new prognostic biomarkers and therapeutic targets for HCC.

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Promoter Hypomethylation and miR-145-5p Downregulation- Mediated HDAC11 Overexpression Promotes Sorafenib Resistance and Metastasis of Hepatocellular Carcinoma Cells

Cited by 30 publications

References 30 publications

DNA Methylation of TGFβ Target Genes: Epigenetic Control of TGFβ Functional Duality in Liver Cancer

DNA Methylation of TGFβ Target Genes: Epigenetic Control of TGFβ Functional Duality in Liver Cancer

HDAC11: a multifaceted histone deacetylase with proficient fatty deacylase activity and its roles in physiological processes

The Role of Non-Coding RNAs in the Sorafenib Resistance of Hepatocellular Carcinoma

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