The Two-Faced Role of SIRT6 in Cancer

Fiorentino, Francesco; Carafa, Vincenzo; Favale, Gregorio; Altucci, Lucia; Mai, Antonello; Rotili, Dante

doi:10.3390/cancers13051156

Cited by 37 publications

(37 citation statements)

References 123 publications

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“… 6 Further investigations indicated that SIRT6 knockout in MEFs leads to tumorigenesis without activation of known oncogenes, and deletion of SIRT6 in vivo correlates with an increased number, size, and aggressiveness of tumors ( Figure 4 ). 8 , 11 The tumor-suppressor role of SIRT6 was associated with the suppression of glycolytic genes crucial for the Warburg effect, a metabolic shift common in cancer cells where ATP is obtained mostly through glycolysis rather than mitochondrial oxidative phosphorylation, in order to generate immediate energy to support fast proliferation and related cellular processes. 58 These genes, including the glucose transporter-1 (GLUT1), lactate dehydrogenase (LDH), phosphofructokinase-1 (PFK1), and pyruvate dehydrogenase kinase-1 (PDK1), are regulated by the hypoxia-inducible factor 1α (HIF-1α), which is corepressed by SIRT6.…”

Section: Biological Functions and Disease Relevance Of Sirt6mentioning

confidence: 99%

“…If we take into account the involvement of SIRT6 in DNA-damage repair, depending on the stage of cancer progression, this pathway may have tumor-promoting or tumor-suppressing effects. 11 Moreover, high levels of SIRT6 associated with tumors may also represent a compensating response rather than a causality. Therefore, it is vital to distinguish the potential of SIRT6 as a therapeutic target or as a biomarker in each type of tumor.…”

Section: Biological Functions and Disease Relevance Of Sirt6mentioning

confidence: 99%

“… 9 Conversely, recent studies also described SIRT6 as a tumor promoter, hence highlighting the context-dependent role of this enzyme in cellular homeostasis. 10 , 11 …”

Section: Introductionmentioning

confidence: 99%

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Emerging Therapeutic Potential of SIRT6 Modulators

2021

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Sirtuin 6 (SIRT6) is an NAD + -dependent protein deacylase and mono-ADP-ribosyltransferase of the sirtuin family with a wide substrate specificity. In vitro and in vivo studies have indicated that SIRT6 overexpression or activation has beneficial effects for cellular processes such as DNA repair, metabolic regulation, and aging. On the other hand, SIRT6 has contrasting roles in cancer, acting either as a tumor suppressor or promoter in a context-specific manner. Given its central role in cellular homeostasis, SIRT6 has emerged as a promising target for the development of small-molecule activators and inhibitors possessing a therapeutic potential in diseases ranging from cancer to age-related disorders. Moreover, specific modulators allow the molecular details of SIRT6 activity to be scrutinized and further validate the enzyme as a pharmacological target. In this Perspective, we summarize the current knowledge about SIRT6 pharmacology and medicinal chemistry and describe the features of the activators and inhibitors identified so far.

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Section: Biological Functions and Disease Relevance Of Sirt6mentioning

confidence: 99%

Section: Biological Functions and Disease Relevance Of Sirt6mentioning

confidence: 99%

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Emerging Therapeutic Potential of SIRT6 Modulators

2021

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“…SIRT6 is found overexpressed in skin cancer and non-small cell lung cancer (NSCLC) [163,164], osteosarcoma, colon carcinoma, serous ovarian cancer and in clear cell renal cell carcinomas (ccRCC) [164][165][166][167][168], showing poor prognostic value. However, in certain types of cancer SIRT6 is classified as a tumor suppressor.…”

Section: Sirtuin Inhibitors Addressing Roles Of Marylating Sirtuins In Cancermentioning

confidence: 99%

“…SIRT6 associates in a phosphorylationdependent form with Ras-GTPase activating protein 1 (G3BP1) [172], with transcription factors BCLAF1, NKRF and THRAP3, the telomerase regulator YLPM1, and the RNA polymerase complex factors COIL and XRN2. The development of small molecules inhibiting specifically either deacetylation or MARylation may provide new clues on SIRT6 functions [178,179,163].…”

Section: Sirtuin Inhibitors Addressing Roles Of Marylating Sirtuins In Cancermentioning

confidence: 99%

Adp-Ribosylation as Post-Translational Modification of Proteins: Use of Inhibitors in Cancer Control

Poltronieri¹,

Misawa²,

Masutani³

2021

Preprint

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Among post-translational modifications of proteins, ADP-ribosylation has been studied for over fifty years, assigning to this PTM a large set of functions, including DNA repair, transcription and cell signaling. This review presents an update on the function of a large set of enzyme writers, the readers that are recruited by the modified targets, and the erasers that reverse the modification to the original amino acid residue, removing the covalent bonds formed. In particular, the review provides details on the involvement of the enzymes performing MAR/PAR cycling in cancers. Of note, there is potential for application of the inhibitors developed for cancer also in the therapy of non-oncological diseases such as the protection against oxidative stress, suppression of inflammatory responses, and the treatment of neurodegenerative diseases. This field of studies is not concluded, since novel enzymes are being discovered at a rapid pace.

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Targeting key proteins involved in transcriptional regulation for cancer therapy: Current strategies and future prospective

Pei

Guo

Peng

et al. 2022

Medicinal Research Reviews

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The key proteins involved in transcriptional regulation play convergent roles in cellular homeostasis, and their dysfunction mediates aberrant gene expressions that underline the hallmarks of tumorigenesis. As tumor progression is dependent on such abnormal regulation of transcription, it is important to discover novel chemical entities as antitumor drugs that target key tumor‐associated proteins involved in transcriptional regulation. Despite most key proteins (especially transcription factors) involved in transcriptional regulation are historically recognized as undruggable targets, multiple targeting approaches at diverse levels of transcriptional regulation, such as epigenetic intervention, inhibition of DNA‐binding of transcriptional factors, and inhibition of the protein–protein interactions (PPIs), have been established in preclinically or clinically studies. In addition, several new approaches have recently been described, such as targeting proteasomal degradation and eliciting synthetic lethality. This review will emphasize on accentuating these developing therapeutic approaches and provide a thorough conspectus of the drug development to target key proteins involved in transcriptional regulation and their impact on future oncotherapy.

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The Two-Faced Role of SIRT6 in Cancer

Cited by 37 publications

References 123 publications

Emerging Therapeutic Potential of SIRT6 Modulators

Emerging Therapeutic Potential of SIRT6 Modulators

Adp-Ribosylation as Post-Translational Modification of Proteins: Use of Inhibitors in Cancer Control

Targeting key proteins involved in transcriptional regulation for cancer therapy: Current strategies and future prospective

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