Researchers discover the role of SIRT7 in the progression of the most common type of lung cancer
The interaction between SIRT7 and ARF, two proteins found in the nucleus of most cells, is key in the progression of Non-Small Cells Lung Cancer, as recently reported by an international team coordinated by Dr. Alessandro Ianni at the Josep Carreras Leukaemia Research Institute and Dr. Thomas Braun at the Max-Planck-Institute for Heart and Lung Research. The findings show that the interaction is independent on the enzymatic activity of SIRT7 and, thus, advocate for therapies aimed at reducing the actual protein levels to reduce tumour expansion, rather than simply inactivating it.
Non-Small Cells Lung Cancer (NSCLC) is the most common type of lung cancer, which is the leading cause of cancer death, accounting for roughly 1.8 million deaths per year, worldwide. From the molecular point of view, many NSCLC display an aberrant balance between the activity of genes promoting cancer progression (called oncogenes) and genes avoiding it (tumour suppressor genes). Among them, SIRT7 and ARF stand out.
Dr. Alessandro Ianni is a senior researcher at the Chromatin Biology Lab of the Josep Carreras Institute, led by Dr. Alejandro Vaquero and he is supported by the prestigious Marie Skłodowska-Curie grant. The group has been studying SIRT7, known for its wide range of functions, for long time. SIRT7 acts as an oncogene in NSCLC, as increased amounts of SIRT7 are related to cell expansion and overall poor prognosis. On the other hand, ARF is a tumour suppressor gene and its activity limits tumour growth and promotes cell death.
The relationship between SIRT7 and ARF had been elusive until the publication of the latest results by Dr. Ianni and Dr. Braun, where they demonstrate that SIRT7 directly binds ARF within the cell’s nucleus in vitro and in vivo, avoiding its stabilisation and, therefore, promoting its degradation. This contact happens in a specialised area of the nucleus, called the nucleolus, and involves a third protein, nucleophosmin (NPM), in charge of stabilising ARF.
The work has been developed by an international scientific team formed by researchers from the previously mentioned groups in collaboration with the University of Vic (Barcelona) and the Nankai University (China). The results of the study, published recently at the prestigious journal PNAS, the official journal of the National Academy of Sciences of the USA, showed a reduced activation of further tumour suppressor genes due to the lower concentration of ARF. On the contrary, the oncogenic activity of SIRT7 effectively unbalance the cell’s equilibrium towards cancer progression. These results have been obtained in cellular models and tumour cells implanted on mice (xenografts), still far from clinical applications.
Furthermore, the researchers found that the simple inactivation of SIRT7 had only limited effect on ARF degradation, meaning that to keep ARF levels up in NSCLC cells, the amount of SIRT7 had to be lowered down for good, not just its activity as had been suggested by others as a possible therapeutic opportunity.
Overall, this could be a groundbreaking study, since not only reveals the mechanisms leading to SIRT7-meditated tumorigenesis in NSCLC – the direct contact with ARF, competing with NPM – but also points towards a possible therapeutic intervention in the form of drugs able to reduce SIRT7 levels, instead of inhibitors, that could significantly impact the treatment of lung cancer in the future.
Reference article: “SIRT7 promotes lung cancer progression by destabilizing the tumor suppressor ARF” Poonam Kumari, Shahriar Tarighi, Eva Fuchshuber, Luhan Li, Irene Fernández-Duran, Meilin Wang, Joshua Ayoson, Jose Manuel Castelló-García, Andrés Gámez-García, Maria Espinosa-Alcantud, Krishnamoorthy Sreenivasan, Stefan Guenther, Mireia Olivella, Rajkumar Savai, Shijing Yue, Alejandro Vaquero, Thomas Braun and Alessandro Ianni June 13, 2024121 (25). https://doi.org/10.1073/pnas.2409269121