SIRT1 deacetylase is overexpressed in human melanoma and its small molecule inhibition imparts anti-proliferative response via p53 activation

Wilking, Melissa J.; Singh, Chandra K.; Nihal, Minakshi; Zhong, Weixiong; Ahmad, Nihal

doi:10.1016/j.abb.2014.04.001

Cited by 70 publications

(64 citation statements)

References 35 publications

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“…However, as we showed in our recent paper, in 65% of the melanoma tissues tested, there was a shift in the localization of SIRT1 to the cytoplasm. 5 Whether this cytoplasmic localization could make such interactions as this one between SIRT1, p300, and SIRT2 more likely remains to be seen. This dynamic interaction could be a new area to explore for possible combinational targeted therapies.…”

Section: Resultsmentioning

confidence: 99%

“…In melanoma cells, chemical inhibition of SIRT1 with the small molecule inhibitor Tenovin-1 led to a decrease in cellular proliferation and viability which was accompanied Keywords: cellular localization, melanoma, PI3K, SIRT1, SIRT1 inhibitors by increased protein levels of p53 and p21. 5 In a few additional experiments we attempted to replicate our findings with other SIRT inhibitors. It is possible that SIRT2 or SIRT3 could be partially responsible for the effects we saw in our previous paper, as they have been shown to play a role in cell cycle regulation and apoptosis.…”

Section: Introductionmentioning

confidence: 88%

“…The role of SIRT1 in melanoma is beginning to be unraveled only recently as 3 separate studies published in 2014, including our own suggested a role for SIRT1 in this deadly neoplasm. 5,7,8 In addition to the finding that SIRT1 inhibition has effects on p53 protein levels in wild-type p53 melanoma cells, another recent paper by our lab found that several other pathways may be affected by SIRT1 inhibition, including a possible role in cell cycle regulation. 9 In our recent paper, we showed that SIRT1 is overexpressed in melanoma cell lines and human tissue samples.…”

Section: Introductionmentioning

confidence: 99%

“…4 In the search for a potential molecular therapeutic target, we recently suggested a possible role for the histone deacetylase SIRT1 in melanoma. 5 SIRT1 is a member of the class III histone deacetylases known as the Sirtuins, which depend on nicotinamide adenine dinucleotide (NADC) as a substrate. SIRT1 has been shown to act through its non-histone protein targets to play a role in a diverse assortment of biological processes, including metabolism, neurodegeneration, and immune function, among others.…”

Section: Introductionmentioning

confidence: 99%

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Sirtuin deacetylases: A new target for melanoma management

et al. 2014

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y These authors contributed equally to this work.M elanoma continues to cause more deaths than any other skin cancer, necessitating the development of new avenues of treatment. One promising new opportunity comes in the form of mechanism-based therapeutic targets. We recently reported the overexpression and delocalization of the class III histone deacetylase SIRT1 in melanoma, and demonstrated that its small molecule inhibition via Tenovin-1 decreased cell growth and viability of melanoma cells, possibly by a p53 mediated induction of p21. Here, we support our data using additional SIRT inhibitors, viz. Sirtinol and Ex-527, which suggests possible benefits of concomitantly inhibiting more than one Sirtuin for an effective cancer management strategy. This "Extra View" paper also includes a discussion of our results in the context of similar recent and concurrent studies. Furthermore, we expand upon our findings in an analysis of new research that may link the cellular localization and growth effects of SIRT1 with the PI3K signaling pathway.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sirtuin deacetylases: A new target for melanoma management

et al. 2014

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“…58 The intricacies of the relationship between SIRT1 and p53 are highlighted by the presence of hyperacetylated p53 in mice lacking SIRT1 59 and tumors overexpressing SIRT1 with inactivated p53. 60,61 Another deacetylase that plays a critical role in modulating the p53 response to genotoxic stress is HDAC5, a class IIa deacetylase. In the early phase of genotoxic stress, HDAC5 binds to and deacetylates p53 at the K120 residue.…”

Section: Different Strokes For Different Folks: P53 Regulation Througmentioning

confidence: 99%

p53 regulation upon genotoxic stress: intricacies and complexities

Kumari

Kohli

Das

2014

Molecular & Cellular Oncology

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These authors contributed equally to this work.Keywords: cancer, genotoxic stress, miRNA, p53, post-translational modifications Abbreviations: miRNA, microRNA; ROS, reactive oxygen species; UTR, untranslated region p53, the revered savior of genomic integrity, receives signals from diverse stress sensors and strategizes to maintain cellular homeostasis. However, the predominance of p53 overshadows the fact that this herculean task is no one-man show; rather, there is a huge army of regulators that reign over p53 at various levels to avoid an unnecessary surge in its levels and sculpt it dynamically to favor one cellular outcome over another. This governance starts right at the time of p53 translation, which is gated by proteins that bind to p53 mRNA and keep a stringent check on p53 protein levels. The same effect is also achieved by ubiquitylases and deubiquitylases that fine-tune p53 turnover and miRNAs that modulate p53 levels, adding precision to this entire scheme. In addition, extensive covalent modifications and differential protein interactions allow p53 to trigger a tailor-made response for a given circumstance. To magnify the marvel, these various tiers of regulation operate simultaneously and in various combinations. In this review, we have tried to provide a glimpse into this bewildering labyrinth. We believe that further studies will result in a better understanding of p53 regulation and that new insights will help unravel many aspects of cancer biology.Regulation of any cellular pathway is essential to coordinate the heterogeneity and complexity of functions in multicellular organisms. Among the tumor suppressors, decoding the bewildering number of pathways that p53 is involved in has long been the holy grail of scientists. p53 is a master regulator that integrates signals from diverse nodes and thus it is of no surprise that it is the most commonly mutated gene in a huge array of cancers with varied origins. p53 has many weapons at its disposal to combat stress including cell cycle arrest, senescence, apoptosis, autophagy, and metabolic reprogramming. Paradoxically, some of the outcomes of p53 activation are disparate and contradictory, such as cell cycle arrest, which is prosurvival, versus apoptosis and senescence, which are directed toward eliminating irreversibly damaged cells. This indicates that p53 needs to be educated to sense the extent and type of damage and make an appropriate choice of the kind of response it is going to elicit. Extensive research on the regulation of p53 under diverse kinds of stresses including genotoxic stress, starvation, hypoxia, and oncogene activation clearly indicate that p53 protein is regulated at diverse levels, including synthesis, degradation, covalent modifications, subcellular localization, and differential interaction with other proteins. Moreover, all possible permutations and combinations of these are employed to modulate p53 specificity, tissue heterogeneity, and diversity of function. In light of this, we restrict this review to exclusively dis...

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Melanoma Metabolism: Molecular Mechanisms and Therapeutic Implications in Cutaneous Oncology

Tan,

Parikh,

Cohen

2024

Cancer Medicine

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BackgroundMelanoma, a highly aggressive skin cancer, is characterized by rapid progression and a high metastatic potential, presenting significant challenges in clinical oncology. A critical aspect of melanoma biology is its metabolic reprogramming, which supports tumor growth, survival, and therapeutic resistance.ObjectiveThis review aims to explore the key molecular mechanisms driving metabolic alterations in melanoma and their implications for developing therapeutic strategies.MethodsA Pubmed search was conducted to analyze literature discussing key mechanisms of the Warburg effect, mitochondrial dysfunction, enhanced lipid metabolism, epigenetic modifications, and the tumor microenvironment.ResultsMetabolic reprogramming supports melanoma growth, proliferation, and survival. Understanding these complex metabolic dynamics provides valuable insights for developing targeted therapeutic strategies.ConclusionPotential therapeutic interventions aimed at disrupting melanoma metabolism highlight the promise of precision medicine in improving treatment outcomes in cutaneous oncology. By targeting metabolic vulnerabilities, novel treatment approaches could significantly enhance the clinical management and prognosis of melanoma.

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SIRT1 deacetylase is overexpressed in human melanoma and its small molecule inhibition imparts anti-proliferative response via p53 activation

Cited by 70 publications

References 35 publications

Sirtuin deacetylases: A new target for melanoma management

Sirtuin deacetylases: A new target for melanoma management

p53 regulation upon genotoxic stress: intricacies and complexities

Melanoma Metabolism: Molecular Mechanisms and Therapeutic Implications in Cutaneous Oncology

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