SIRT7 promotes lung cancer progression by destabilizing the tumor suppressor ARF.

Sirtuin 7 (SIRT7) is a member of the mammalian family of nicotinamide adenine dinucleotide (NAD+)-dependent histone/protein deacetylases, known as sirtuins. It acts as a potent oncogene in numerous malignancies, but the molecular mechanisms employed by SIRT7 to sustain lung cancer progression remain largely uncharacterized. We demonstrate that SIRT7 exerts oncogenic functions in lung cancer cells by destabilizing the tumor suppressor alternative reading frame (ARF). SIRT7 directly interacts with ARF and prevents binding of ARF to nucleophosmin, thereby promoting proteasomal-dependent degradation of ARF. We show that SIRT7-mediated degradation of ARF increases expression of protumorigenic genes and stimulates proliferation of non-small-cell lung cancer (NSCLC) cells both in vitro and in vivo in a mouse xenograft model. Bioinformatics analysis of transcriptome data from human lung adenocarcinomas revealed a correlation between SIRT7 expression and increased activity of genes normally repressed by ARF. We propose that disruption of SIRT7-ARF signaling stabilizes ARF and thus attenuates cancer cell proliferation, offering a strategy to mitigate NSCLC progression.

SIRT7: a novel molecular target for personalized cancer treatment?

The Sirtuin family of NAD+-dependent enzymes assumes a pivotal role in orchestrating adaptive responses to environmental fluctuations and stress stimuli, operating at both genomic and metabolic levels. Within this family, SIRT7 emerges as a versatile player in tumorigenesis, displaying both pro-tumorigenic and tumor-suppressive functions in a context-dependent manner. While other sirtuins, such as SIRT1 and SIRT6, exhibit a similar dual role in cancer, SIRT7 stands out due to distinctive attributes that sharply distinguish it from other family members. Among these are a unique key role in regulation of nucleolar functions, a close functional relationship with RNA metabolism and processing -exceptional among sirtuins- and a complex multienzymatic nature, which provides a diverse range of molecular targets. This review offers a comprehensive overview of the current understanding of the role of SIRT7 in various malignancies, placing particular emphasis on the intricate molecular mechanisms employed by SIRT7 to either stimulate or counteract tumorigenesis. Additionally, it delves into the unique features of SIRT7, discussing their potential and specific implications in tumor initiation and progression, underscoring the promising avenue of targeting SIRT7 for the development of innovative anti-cancer therapies.

The SIRT7-nucleolus connection in cancer: ARF enters the fray.

The nucleolar enzyme sirtuin 7 (SIRT7) promotes cancer progression in certain malignancies, likely in part by controlling ribosome biosynthesis. Recently, we discovered that SIRT7 destabilizes the cyclin dependent kinase inhibitor 2A (CDKN2A, known as ARF) within the nucleolus, aiding cancer progression. We propose that targeting nucleolar SIRT7 offers promise for new anti-cancer therapies.

SIRT7 and p53 interaction in embryonic development and tumorigenesis.

p53 is a hallmark tumor suppressor due in part to its role in cell cycle progression, DNA damage repair, and cellular apoptosis; its protein activity interrelates with the Sirtuin family of proteins, major regulators of the cellular response to metabolic, oxidative, and genotoxic stress. In the recent years, mammalian Sirtuin 7 (SIRT7) has emerged as a pivotal regulator of p53, fine-tuning its activity in a context dependent manner. SIRT7 is frequently overexpressed in human cancer, yet its precise role in tumorigenesis and whether it involves p53 regulation is insufficiently understood. Depletion of SIRT7 in mice results in impaired embryo development and premature aging. While p53 activity has been suggested to contribute to tissue specific dysfunction in adult Sirt7 -/- mice, whether this also applies during development is currently unknown. By generating SIRT7 and p53 double-knockout mice, here we show that the demise of SIRT7-deficient embryos is not the result of p53 activity. Notably, although SIRT7 is commonly considered an oncogene, SIRT7 haploinsufficiency increases tumorigenesis in p53 knockout mice. Remarkably, in specific human tumors harboring p53 mutation, we identified that SIRT7 low expression correlates with poor patient prognosis. Transcriptomic analysis unveils a previously unrecognized interplay between SIRT7 and p53 in epithelial-to-mesenchymal transition (EMT) and extracellular matrix regulation with major implications for our understanding of embryonic development and tumor progression.