SIRT1 ISGylation accelerates tumor progression by unleashing SIRT1 from the inactive state to promote its deacetylase activity

ISG15 is an interferon-stimulated ubiquitin-like protein (UBL) with multifaceted roles as a posttranslational modifier in ISG15 conjugation (ISGylation). However, the mechanistic consequences of ISGylation in cancer have not been fully elucidated, largely due to a lack of knowledge on the ISG15 target repertoire. Here, we identified SIRT1, a nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase, as a new target for ISGylation. SIRT1 ISGylation impairs the association of SIRT1 with its negative regulator, deleted in breast cancer 1 (DBC1), which unleashes SIRT1 from its inactive state and leads to an increase in its deacetylase activity. Importantly, SIRT1 ISGylation promoted lung cancer progression and limited lung cancer cell sensitivity to DNA damage-based therapeutics in vivo and in vitro models. The levels of ISG15 mRNA and protein were significantly higher in lung cancer tissues than in adjacent normal tissues. Accordingly, elevated expression of SIRT1 and ISG15 was associated with poor prognosis in lung cancer patients, a finding that could be translated for lung cancer patient stratification and disease outcome evaluation. Taken together, our findings provide a mechanistic understanding of the regulatory effect of SIRT1 ISGylation on tumor progression and therapeutic efficacy in lung cancer. Interferon-stimulated gene 15 (ISG15) is known to influence tumor growth and severity. Young Joo Jeon at Chungnam National University College of Medicine, Daejon, South Korea, and co-workers found that ISG15 can conjugate to another protein, SIRT1, which also affects tumor growth and response to treatment. The research, conducted on human cells, mice, and human lung cancer tissues, revealed that when ISG15 conjugates to SIRT1, it boosts SIRT1's activity, encouraging tumor growth and reducing the effectiveness of a chemotherapy drug. Additionally, high levels of SIRT1 and ISG15 in lung cancer tissues were linked to worse outcomes. The study suggests that focusing on understanding of the regulatory effect of ISG15 conjugation to SIRT1 could enhance cancer treatments. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.