The Deubiquitinase USP13 Maintains Cancer Cell Stemness by Promoting FASN Stability in Small Cell Lung Cancer

Abstract

USP13 is significantly amplified in over 20% of lung cancer patients and critical for tumor progression. However, the functional role of USP13 in small cell lung cancer (SCLC) remains largely unclear. In this study, we found that the deubiquitinase USP13 is highly expressed in SCLC tumor samples and positively associated with poor prognosis in multiple cohorts. In vitro and in vivo depletion of USP13 inhibited SCLC cancer stem cells (CSCs) properties and tumorigenesis, and this inhibitory effect was rescued by reconstituted expression of wide type (WT) USP13 but not the enzyme-inactive USP13 mutant. Mechanistically, USP13 interacts with fatty acid synthase (FASN) and enhances FASN protein stability. FASN downregulation suppresses USP13-enhanced cell renewal regulator expression, sphere formation ability, and de novo fatty acids biogenesis. Accordingly, we found FASN expression is upregulated in surgical resected SCLC specimens, positively correlated with USP13, and associated with poor prognosis of SCLC patients. More importantly, the small molecule inhibitor of FASN, TVB-2640, significantly inhibits lipogenic phenotype and attenuates self-renewal ability, chemotherapy resistance and USP13-mediated tumorigenesis in SCLC. Thus, our study highlights a critical role of the USP13-FASN-lipogenesis axis in SCLC cancer stemness maintenance and tumor growth, and reveals a potential combination therapy for SCLC patients.

The pro-tumorigenic cytokine IL-32 has a high turnover in multiple myeloma cells due to proteolysis regulated by oxygen-sensing cysteine dioxygenase and deubiquitinating enzymes

“…IL-32 is highly expressed by activated T cells ( 35 – 38 ). DUBs are currently exploited as therapeutic targets in different cancers ( 23 , 39 – 41 ), but they may also influence the cancer microenvironment, including T cells ( 42 ). Our data show that the use of proteasome inhibitors and DUB inhibitors affects IL-32 protein levels in T cells, which should be kept in mind when using DUB inhibitors in cancer treatments.…”

Metabolic reprogramming of clear cell renal cell carcinoma

“…TVB-2640 is a noval FAS inhibitor that has shown great promise in clinical studies ( 100 ). In a phase I clinical trial, TVB-2640 effectively reduced fatty acid production in patients with non-small cell lung cancer.…”

Roles of ubiquitin‑specific protease 13 in normal physiology and tumors (Review)

“…USP13 is dysregulated in various tumors and can therefore be a good prognostic marker in tumors. USP13 has been shown to upregulate fatty acid synthase (FASN) to promote the proliferation of SCLC cells and Twist-related protein 1 (Twist1) to promote the migration and invasion of breast cancer cells, while it inhibits cell proliferation via downregulation of glycolysis in oral squamous cell carcinoma ( 47 , 48 ).…”

“…USP13 promotes the growth of SCLC cells by maintaining the expression of FASN through the ubiquitin-proteasome pathway. This process could be rescued by FASN inhibition ( 47 ).…”