Senescence and immortality in hepatocellular carcinoma

Öztürk, Mehmet; Arslan-Ergül, Ayça; Bağişlar, Sevgi; Şentürk, Şerif; Yuzugullu, Haluk

doi:10.1016/j.canlet.2008.10.048

Cited by 76 publications

(58 citation statements)

References 91 publications

(109 reference statements)

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“…Telomeres are shortened on every DNA replication cycle due to the requirement of short RNA to prime DNA synthesis by DNA polymerases (38). Progressive telomere shortening is also found in chronic liver injury and liver cirrhosis (39). Telomere shortening triggers the DNA damage response, leading to cell-cycle arrest, senescence, or apoptosis (40), and it also serves as a tumor suppressor mechanism to limit the proliferation of transformed cells.…”

Section: Discussionmentioning

confidence: 99%

“…Telomere shortening triggers the DNA damage response, leading to cell-cycle arrest, senescence, or apoptosis (40), and it also serves as a tumor suppressor mechanism to limit the proliferation of transformed cells. Nevertheless, TERT is activated in most tumors including HCC to overcome the telomere barrier by adding back telomere repeats to chromosome ends (39). Inhibition of TERT shortens telomeres and causes cancer cell death (41).…”

Section: Discussionmentioning

confidence: 99%

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Sirtuin 1 Is Upregulated in a Subset of Hepatocellular Carcinomas where It Is Essential for Telomere Maintenance and Tumor Cell Growth

et al. 2011

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Hepatocellular carcinoma (HCC) is a highly malignant tumor with a poor prognosis. Treatment of HCC is complicated by the fact that the disease is often diagnosed at an advanced stage when it is no longer amenable to curative surgery, and current systemic chemotherapeutics are mostly inefficacious. Sirtuin 1 (SIRT1) is a class III histone deacetylase that is implicated in gene regulations and stress resistance. In this study, we found that SIRT1 is essential for the tumorigenesis of HCC. We showed that although SIRT1 was expressed at very low levels in normal livers, it was overexpressed in HCC cell lines and in a subset of HCC. Tissue microarray analysis of HCC and adjacent nontumoral liver tissues revealed a positive correlation between the expression levels of SIRT1 and advancement in tumor grades. Downregulation of SIRT1 consistently suppressed the proliferation of HCC cells via the induction of cellular senescence or apoptosis. SIRT1 silencing also caused telomere dysfunction-induced foci and nuclear abnormality that were clearly associated with reduced expressions of telomerase reverse transcriptase (TERT), and PTOP, which is a member of the shelterin complex. Ectopic expression of either TERT or PTOP in SIRT1-depleted cells significantly restored cell proliferation. There was also a positive correlation between the level of induction of SIRT1 and PTOP in human HCC. Finally, SIRT1-silencing sensitized HCC cells to doxorubicin treatment. Together, our findings reveal a novel function for SIRT1 in telomere maintenance of HCC, and they rationalize the clinical exploration of SIRT1 inhibitors for HCC therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Sirtuin 1 Is Upregulated in a Subset of Hepatocellular Carcinomas where It Is Essential for Telomere Maintenance and Tumor Cell Growth

et al. 2011

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“…Hepatocellular carcinoma cells (HCC) are known to overexpress several oncogenes and also down-regulate tumour suppressor genes [43,44]. Vitamin K2, in the form of menaquinone-4, has been investigated for its growth regulating effects in three hepatocellular cancer cell lines [45].…”

Section: Nf-κb and Vitamin Kmentioning

confidence: 99%

Anti-Inflammatory Actions of Vitamin K

Hodges¹,

Pitsillides²,

Ytrebø³

et al. 2017

Vitamin K2 - Vital for Health and Wellbeing

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Naphthoquinone compounds have received attention for their ability to regulate diseases from bacterial and parasite infections through to chronic human diseases. Inflammation is widely considered to be at the root of many chronic diseases. The reports of anti-inflammatory activity of naphthoquinones, including vitamin K1 (phylloquinone) and vitamin K2s (menaquinones), are of interest due to their very low toxicity. Most of the evidence for the anti-inflammatory mechanisms of vitamin K suggests a role in the inhibition of the cell signalling complex nuclear factor kappa-B (NF-κB).

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“…Cancer rates and etiology of HCC vary considerably by age, gender, ethnic origin, lifestyle (in particular alcohol abuse [209]) and environmental pollution [210]. Other factors include the infection by hepatitis B and C virus (HBV and HCV) [211,212], exposure to aflatoxins, hypertension and diabetes [210,213]. Both genetic and epigenetic factors form the molecular basis of HCC.…”

Section: Livermentioning

confidence: 99%

“…Both genetic and epigenetic factors form the molecular basis of HCC. Epigenetic alterations may predispose to genetic changes and, vice versa, genetic changes may also initiate aberrant epigenetic modifications [210,[213][214][215][216]. DNA methylation and various histone modifications, as well as RNA interference, have been reported as epigenetic events contributing to HCC development [210,215,217].…”

Section: Livermentioning

confidence: 99%

Modulation of Epigenetic Targets for Anticancer Therapy: Clinicopathological Relevance, Structural Data and Drug Discovery Perspectives

Andreoli¹,

Barbosa²,

Parenti³

et al. 2012

CPD

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Abstract:Research on cancer epigenetics has flourished in the last decade. Nevertheless growing evidence point on the importance to understand the mechanisms by which epigenetic changes regulate the genesis and progression of cancer growth. Several epigenetic targets have been discovered and are currently under validation for new anticancer therapies. Drug discovery approaches aiming to target these epigenetic enzymes with small-molecules inhibitors have produced the first pre-clinical and clinical outcomes and many other compounds are now entering the pipeline as new candidate epidrugs. The most studied targets can be ascribed to histone deacetylases and DNA methyltransferases, although several other classes of enzymes are able to operate post-translational modifications to histone tails are also likely to represent new frontiers for therapeutic interventions. By acknowledging that the field of cancer epigenetics is evolving with an impressive rate of new findings, with this review we aim to provide a current overview of pre-clinical applications of smallmolecules for cancer pathologies, combining them with the current knowledge of epigenetic targets in terms of available structural data and drug design perspectives.Keywords: Epigenetics, anticancer therapy, DNA methyltransferases, protein methyltransferases, demethylases, deacetylases, acetyltransferases, histone post-translational modifications, drug design, crystallography, small-molecule inhibitors. INTRODUCTIONThe term epigenetics currently refers to the mechanisms of temporal and spatial control of gene activity that do not depend on the DNA sequence, influencing the physiological and pathological development of an organism. The molecular mechanisms by which epigenetic changes occur are complex and cover a wide range of processes including paramutation, bookmarking, imprinting, gene silencing, carcinogenesis progression, and, most importantly, regulation of heterochromatin and histone modifications [1]. At a biochemical level, epigenetic alterations in chromatin involve methylation of DNA patterns, several forms of histone modifications and microRNA (miRNA) expression. All these processes modulate the structure of chromatin leading to the activation or silencing of gene expression [2][3][4][5][6]. More specifically, the chromatin remodeling is accomplished by two main mechanisms that concern the methylation of cytosine residues in DNA and a variety of post-translational modifications (PTMs) occurring at the N-terminal tails of histone proteins. These PTMs include acetylation, methylation, phosphorylation, ubiquitylation, sumoylation, glycosylation, ADPribosylation, carbonylation, citrullination and biotinylation [7,8]. Among all PTMs for example, histone tails can have its lysine residues acetylated, methylated or ubiquitilated; arginine can be methylated; serine and threonine residues can be phosphorylated [9][10][11][12][13][14][15][16][17]. These covalent modifications are able to cause other PTMs and the ensemble of this cross-talk is known as the his...

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Senescence and immortality in hepatocellular carcinoma

Cited by 76 publications

References 91 publications

Sirtuin 1 Is Upregulated in a Subset of Hepatocellular Carcinomas where It Is Essential for Telomere Maintenance and Tumor Cell Growth

Sirtuin 1 Is Upregulated in a Subset of Hepatocellular Carcinomas where It Is Essential for Telomere Maintenance and Tumor Cell Growth

Anti-Inflammatory Actions of Vitamin K

Modulation of Epigenetic Targets for Anticancer Therapy: Clinicopathological Relevance, Structural Data and Drug Discovery Perspectives

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