Periodic Reporting for period 1 - SIRT7-LC (Role of the SIRT7-NPM-c-Myc pathway in lung cancer)
Okres sprawozdawczy: 2023-09-01 do 2025-08-31
Lung cancer remains one of the most devastating diseases worldwide and is the leading cause of cancer-related death in both men and women. Within the European Union, it ranks as the third most common cancer among women and the second among men. Despite advances in diagnosis and treatment, the survival rate of lung cancer patients remains alarmingly low, with fewer than one in five individuals surviving more than five years after diagnosis. Understanding the molecular mechanisms that drive this disease is therefore crucial for developing more effective and personalized therapeutic strategies.
In recent years, a family of enzymes known as sirtuins has attracted increasing attention for their ability to regulate essential cellular processes such as metabolism, stress response, and genome stability. Among them, Sirtuin 7 (SIRT7) has emerged as a complex and multifunctional enzyme capable of acting either as a promoter or a suppressor of tumor progression, depending on the cellular context. However, its precise role in lung cancer advancement remains poorly understood.
SIRT7 is primarily located in the nucleolus, a compartment within the cell nucleus that—beyond its classical role in ribosome production—is now recognized as a key coordinator of processes linked to cancer initiation and development. By regulating proteins that control cell growth and stress responses, the nucleolus functions as a central hub in tumor biology. This evidence suggests that SIRT7 may influence lung cancer advancement, at least in part, by controlling these nucleolar functions.
The SIRT7-LC project was established to investigate how SIRT7 contributes to lung cancer development and to identify the molecular mechanisms through which it exerts its effects. In particular, the project explored how SIRT7 modulates the activity of nucleophosmin (NPM), a multifunctional nucleolar protein that finely regulates the balance between tumor-suppressive and pro-oncogenic factors within the nucleolus, thereby affecting cancer cell growth and survival.
Specifically, the overall objective of SIRT7-LC was to gain a deeper understanding of how SIRT7-mediated deregulation of nucleolar functions influences lung cancer progression, and to assess whether targeting SIRT7 could represent a viable strategy to limit disease advancement and improve patient outcomes.
In recent years, a family of enzymes known as sirtuins has attracted increasing attention for their ability to regulate essential cellular processes such as metabolism, stress response, and genome stability. Among them, Sirtuin 7 (SIRT7) has emerged as a complex and multifunctional enzyme capable of acting either as a promoter or a suppressor of tumor progression, depending on the cellular context. However, its precise role in lung cancer advancement remains poorly understood.
SIRT7 is primarily located in the nucleolus, a compartment within the cell nucleus that—beyond its classical role in ribosome production—is now recognized as a key coordinator of processes linked to cancer initiation and development. By regulating proteins that control cell growth and stress responses, the nucleolus functions as a central hub in tumor biology. This evidence suggests that SIRT7 may influence lung cancer advancement, at least in part, by controlling these nucleolar functions.
The SIRT7-LC project was established to investigate how SIRT7 contributes to lung cancer development and to identify the molecular mechanisms through which it exerts its effects. In particular, the project explored how SIRT7 modulates the activity of nucleophosmin (NPM), a multifunctional nucleolar protein that finely regulates the balance between tumor-suppressive and pro-oncogenic factors within the nucleolus, thereby affecting cancer cell growth and survival.
Specifically, the overall objective of SIRT7-LC was to gain a deeper understanding of how SIRT7-mediated deregulation of nucleolar functions influences lung cancer progression, and to assess whether targeting SIRT7 could represent a viable strategy to limit disease advancement and improve patient outcomes.
Building on these objectives, the SIRT7-LC project carried out an extensive experimental program to investigate how SIRT7 contributes to lung cancer development and to evaluate its potential as a therapeutic target. Using human lung cancer cell models, xenograft assays, and genetically engineered mice in which SIRT7 was selectively inhibited, the project demonstrated that this enzyme functions as a major promoter of tumor progression. Importantly, inhibition of SIRT7 markedly retarded tumor growth, confirming its critical role in driving lung cancer progression. Analyses of patient-derived lung cancer specimens further reinforced these findings, revealing that SIRT7 expression is markedly increased in tumors compared with healthy lung tissues, underscoring its potential clinical relevance.
At the mechanistic level, a comprehensive set of biochemical studies revealed that SIRT7 interferes with the function of key tumor suppressor proteins within the nucleolus by preventing their proper interaction with the multifunctional protein nucleophosmin (NPM). This disruption destabilizes these tumor suppressors, making them more prone to degradation and shifting the cellular balance toward activation of pro-tumorigenic signaling pathways that fuel cancer progression. Interestingly, these functions are mediated through mechanisms that do not require SIRT7 catalytic activity.
Collectively, the findings of SIRT7-LC identify SIRT7 as a central regulator of nucleolar homeostasis in cancer and a promising molecular target for therapeutic intervention. By uncovering previously unknown molecular pathways that drive tumor growth, the project provides groundbreaking insights into the biology of lung cancer. The project establishes a robust experimental foundation for future studies aimed at translating these discoveries into more effective and personalized treatment strategies for lung cancer patients. Together, these results offer compelling evidence that targeting SIRT7 could enable innovative therapeutic approaches with tangible patient benefits, ultimately helping to reduce the medical and socio-economic burden of cancer across Europe.
At the mechanistic level, a comprehensive set of biochemical studies revealed that SIRT7 interferes with the function of key tumor suppressor proteins within the nucleolus by preventing their proper interaction with the multifunctional protein nucleophosmin (NPM). This disruption destabilizes these tumor suppressors, making them more prone to degradation and shifting the cellular balance toward activation of pro-tumorigenic signaling pathways that fuel cancer progression. Interestingly, these functions are mediated through mechanisms that do not require SIRT7 catalytic activity.
Collectively, the findings of SIRT7-LC identify SIRT7 as a central regulator of nucleolar homeostasis in cancer and a promising molecular target for therapeutic intervention. By uncovering previously unknown molecular pathways that drive tumor growth, the project provides groundbreaking insights into the biology of lung cancer. The project establishes a robust experimental foundation for future studies aimed at translating these discoveries into more effective and personalized treatment strategies for lung cancer patients. Together, these results offer compelling evidence that targeting SIRT7 could enable innovative therapeutic approaches with tangible patient benefits, ultimately helping to reduce the medical and socio-economic burden of cancer across Europe.
SIRT7-LC has provided novel insights into how nucleolar dysfunction drives tumorigenesis. The finding that SIRT7 destabilizes key tumor suppressors by disrupting their nucleolar retention mechanisms constitutes a conceptual advance in understanding the contribution of the nucleolus to cancer development. These discoveries open new research avenues into how nucleolar proteins coordinate stress signaling, oncogene activation, and tumor suppression.
While inhibitors of SIRT7 enzymatic activity have recently shown efficacy in slowing the progression of certain malignancies, SIRT7-LC uncovered a previously unrecognized enzyme-independent role of SIRT7 in cancer biology. This observation suggests that therapeutic strategies focused on disrupting SIRT7’s protein–protein interactions or promoting SIRT7 protein degradation, rather than solely inhibiting its catalytic activity, may offer a more effective approach to suppress tumor growth in specific cancer types.
Future pre-clinical and clinical studies will be crucial to validate this hypothesis and to define the most promising therapeutic strategies for targeting SIRT7 as an anticancer intervention.
While inhibitors of SIRT7 enzymatic activity have recently shown efficacy in slowing the progression of certain malignancies, SIRT7-LC uncovered a previously unrecognized enzyme-independent role of SIRT7 in cancer biology. This observation suggests that therapeutic strategies focused on disrupting SIRT7’s protein–protein interactions or promoting SIRT7 protein degradation, rather than solely inhibiting its catalytic activity, may offer a more effective approach to suppress tumor growth in specific cancer types.
Future pre-clinical and clinical studies will be crucial to validate this hypothesis and to define the most promising therapeutic strategies for targeting SIRT7 as an anticancer intervention.