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.

Protein Quality Control in the Endoplasmic Reticulum and Cancer.

The endoplasmic reticulum (ER) is an essential compartment of the biosynthesis, folding, assembly, and trafficking of secretory and transmembrane proteins, and consequently, eukaryotic cells possess specialized machineries to ensure that the ER enables the proteins to acquire adequate folding and maturation for maintaining protein homeostasis, a process which is termed proteostasis. However, a large variety of physiological and pathological perturbations lead to the accumulation of misfolded proteins in the ER, which is referred to as ER stress. To resolve ER stress and restore proteostasis, cells have evolutionary conserved protein quality-control machineries of the ER, consisting of the unfolded protein response (UPR) of the ER, ER-associated degradation (ERAD), and autophagy. Furthermore, protein quality-control machineries of the ER play pivotal roles in the control of differentiation, progression of cell cycle, inflammation, immunity, and aging. Therefore, severe and non-resolvable ER stress is closely associated with tumor development, aggressiveness, and response to therapies for cancer. In this review, we highlight current knowledge in the molecular understanding and physiological relevance of protein quality control of the ER and discuss new insights into how protein quality control of the ER is implicated in the pathogenesis of cancer, which could contribute to therapeutic intervention in cancer.

ISG15 in cancer: Beyond ubiquitin-like protein.

ISG15, the product of interferon (IFN)-stimulated gene 15, is the first identified ubiquitin-like protein (Ubl), playing roles not only as an unconjugated form but also as a covalently conjugated form onto a target protein. ISG15 is not present in lower eukaryotes such as yeast, nematode (Caenorhabditis), or insect (Drosophila), indicating that the functions of ISG15 and ISG15 conjugation (ISGylation) are restricted to higher eukaryotes and have evolved with IFN signaling. Despite the highlighted complexity of ISG15 and ISGylation, increasing evidences have been emerging that ISG15 and ISGylation are implicated in a variety of pivotal cellular processes, involving protein translation, autophagy, exosome secretion, DNA repair, and immune modulation, which emphasizes the necessity of re-evaluation of ISG15 and ISGylation. In this review, we highlight current knowledge in the molecular understanding and physiological relevance of ISG15 and ISGylation and discuss new insights into how ISG15 is implicated in the pathogenesis of cancer, which could contribute to therapeutic intervention in cancer.

Comparison of operative mortality and complications between bronchoplastic lobectomy and pneumonectomy in lung cancer patients.

Bronchoplastic lobectomy is a lung-saving procedure indicated for central tumors, for which the alternative is pneumonectomy. We compared operative mortality and complications between bronchoplastic lobectomy and pneumonectomy in lung cancer patients. From March 1993 through December 2005, 1,461 patients were surgically resected for non-small cell lung cancer, including 73 who underwent bronchoplastic lobectomy and 258 who underwent pneumonectomy. Bronchoplastic lobectomy was performed on any lesion that could be completely resected by this technique, whereas pneumonectomy was only performed on lesions that could not be removed by bronchoplastic lobectomy. Operative deaths occurred in 1 of 73 (1.4%) bronchoplastic lobectomy and 26 of 258 (10.1%) pneumonectomy patients (p=0.014). Major complications occurred in 16 of 73 (21.9%) bronchoplastic lobectomy and 58 of 258 (22.5%) pneumonectomy patients (p=1.0). Bronchoplastic lobectomy has a lower risk of operative mortality than pneumonectomy. Although the complication rates were similar, bronchoplastic lobectomy was associated with improved postoperative cardiopulmonary status and a low prevalence of fatal complications after bronchial anastomosis. These findings indicate that bronchoplastic lobectomy is a valuable alternative to pneumonectomy for anatomically appropriate patients, regardless of underlying cardiopulmonary function.