USP28 controls SREBP2 and the mevalonate pathway to drive tumour growth in squamous cancer

Maier, Carina R.; Hartmann, Oliver; Prieto-Garcia, Cristian; Al-Shami, Kamal M.; Schlicker, Lisa; Vogel, Felix C. E.; Haid, Sibylle; Klann, Kevin; Buck, Viktoria; Münch, Christian; Schmitz, W.; Einig, Elias; Krenz, Bastian; Calzado, Marco A.; Eilers, Martin; Popov, Nikita; Rosenfeldt, Mathias T.; Diefenbacher, Markus E.; Schulze, Almut

doi:10.1038/s41418-023-01173-6

Cited by 9 publications

(2 citation statements)

References 56 publications

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“…Knockdown of USP28 using two distinct shRNAs did not result in any observable impact on the associated deubiquitinase USP25, despite the significant structural similarities between the two enzymes (Figure S1B). 40,43 We next examined the interaction between USP28 and ICN1 in HEK293T cells to confirm that USP28 is a deubiquitinase for ICN1 in our experiment. An immunoprecipitation assay with ectopically expressed Flag‐ICN1 showed a pulldown of endogenous USP28 (Figure 1B), verifying an interaction between the two proteins.…”

Section: Resultsmentioning

confidence: 75%

Preclinical testing of CT1113, a novel USP28 inhibitor, for the treatment of T‐cell acute lymphoblastic leukaemia

Xu,

Peng,

Sun

et al. 2024

Br J Haematol

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SummaryT‐cell acute lymphoblastic leukaemia (T‐ALL) is a highly aggressive and heterogeneous lymphoid malignancy with poor prognosis in adult patients. Aberrant activation of the NOTCH1 signalling pathway is involved in the pathogenesis of over 60% of T‐ALL cases. Ubiquitin‐specific protease 28 (USP28) is a deubiquitinase known to regulate the stability of NOTCH1. Here, we report that genetic depletion of USP28 or using CT1113, a potent small molecule targeting USP28, can strongly destabilize NOTCH1 and inhibit the growth of T‐ALL cells. Moreover, we show that USP28 also regulates the stability of sterol regulatory element binding protein 1 (SREBP1), which has been reported to mediate increased lipogenesis in tumour cells. As the most critical transcription factor involved in regulating lipogenesis, SREBP1 plays an important role in the metabolism of T‐ALL. Therefore, USP28 may be a potential therapeutic target, and CT1113 may be a promising novel drug for T‐ALL with or without mutant NOTCH1.

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Section: Resultsmentioning

confidence: 75%

Preclinical testing of CT1113, a novel USP28 inhibitor, for the treatment of T‐cell acute lymphoblastic leukaemia

Xu,

Peng,

Sun

et al. 2024

Br J Haematol

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“…Another rate-limiting enzyme in the mevalonate pathway is hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR). HMGCR as a target for fluvastatin, a statin medicine against cholesterol and cardiovascular diseases, suppressed NSCLC cell growth and induced apoptosis [ 153 ]. Moreover, cerivastatin of the mevalonate pathway has anti-cancer activity against ALK tyrosine kinase inhibitors (ALK-TKIs) resistance both in vitro and in vivo.…”

Section: Blocking Common Nsclc Metabolic Pathways As Anti-nsclcmentioning

confidence: 99%

Energy metabolism as the hub of advanced non-small cell lung cancer management: a comprehensive view in the framework of predictive, preventive, and personalized medicine

Bajinka,

Ouedraogo,

Golubnitschaja

et al. 2024

EPMA Journal

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Energy metabolism is a hub of governing all processes at cellular and organismal levels such as, on one hand, reparable vs. irreparable cell damage, cell fate (proliferation, survival, apoptosis, malignant transformation etc.), and, on the other hand, carcinogenesis, tumor development, progression and metastazing versus anti-cancer protection and cure. The orchestrator is the mitochondria who produce, store and invest energy, conduct intracellular and systemically relevant signals decisive for internal and environmental stress adaptation, and coordinate corresponding processes at cellular and organismal levels. Consequently, the quality of mitochondrial health and homeostasis is a reliable target for health risk assessment at the stage of reversible damage to the health followed by cost-effective personalized protection against health-to-disease transition as well as for targeted protection against the disease progression (secondary care of cancer patients against growing primary tumors and metastatic disease).The energy reprogramming of non-small cell lung cancer (NSCLC) attracts particular attention as clinically relevant and instrumental for the paradigm change from reactive medical services to predictive, preventive and personalized medicine (3PM). This article provides a detailed overview towards mechanisms and biological pathways involving metabolic reprogramming (MR) with respect to inhibiting the synthesis of biomolecules and blocking common NSCLC metabolic pathways as anti-NSCLC therapeutic strategies. For instance, mitophagy recycles macromolecules to yield mitochondrial substrates for energy homeostasis and nucleotide synthesis. Histone modification and DNA methylation can predict the onset of diseases, and plasma C7 analysis is an efficient medical service potentially resulting in an optimized healthcare economy in corresponding areas. The MEMP scoring provides the guidance for immunotherapy, prognostic assessment, and anti-cancer drug development. Metabolite sensing mechanisms of nutrients and their derivatives are potential MR-related therapy in NSCLC. Moreover, miR-495-3p reprogramming of sphingolipid rheostat by targeting Sphk1, 22/FOXM1 axis regulation, and A2 receptor antagonist are highly promising therapy strategies. TFEB as a biomarker in predicting immune checkpoint blockade and redox-related lncRNA prognostic signature (redox-LPS) are considered reliable predictive approaches.Finally, exemplified in this article metabolic phenotyping is instrumental for innovative population screening, health risk assessment, predictive multi-level diagnostics, targeted prevention, and treatment algorithms tailored to personalized patient profiles—all are essential pillars in the paradigm change from reactive medical services to 3PM approach in overall management of lung cancers. This article highlights the 3PM relevant innovation focused on energy metabolism as the hub to advance NSCLC management benefiting vulnerable subpopulations, affected patients, and healthcare at large.

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Targeting piRNA‐137463 Inhibits Tumor Progression and Boosts Sensitivity to Immune Checkpoint Blockade via De Novo Cholesterol Biosynthesis in Lung Adenocarcinoma

Zhan,

Tian,

Fan

et al. 2024

Advanced Science

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The important role of PIWI‐interacting RNAs (piRNAs) in tumors has garnered increasing attention. However, research on their role in lung adenocarcinoma (LUAD) remains limited. Elevated levels of piRNA‐137463 have been linked to poor prognosis in LUAD patients. Inhibition of piRNA‐137463 curbed the proliferation, migration, and invasion of LUAD cells, enhanced T cell cytotoxicity through increased IFN‐γ secretion, disrupted cholesterol metabolism, and reduced intracellular cholesterol, lipid raft content, and PD‐L1 expression in LUAD cells. Bioinformatic prediction identified a potential interaction between piRNA‐137463 and lncRNA LOC100128494. Inhibiting piRNA‐137463 increased the stability and expression of LOC100128494, which further modulated insulin‐induced gene 1 protein (INSIG1) levels via a competitive endogenous RNA network involving LOC100128494 and miR‐24‐3p. Notably, the effect of piRNA‐137463 in LUAD cells is dependent on the expression of LOC100128494 and INSIG1. Inhibiting the expression of piRNA‐137463 with AntagopiRNA‐137463 suppressed tumor growth and metastasis via LOC100128494 in nude mice and enhanced the response of LUAD to anti‐PD‐1 therapy in immune‐competent mice. In summary, this study elucidates the role of piRNA‐137463 in the reprogramming of cholesterol metabolism, which drives the progression of LUAD, thereby identifying a new target for the comprehensive clinical management of LUAD.

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USP28 controls SREBP2 and the mevalonate pathway to drive tumour growth in squamous cancer

Cited by 9 publications

References 56 publications

Preclinical testing of CT1113, a novel USP28 inhibitor, for the treatment of T‐cell acute lymphoblastic leukaemia

Preclinical testing of CT1113, a novel USP28 inhibitor, for the treatment of T‐cell acute lymphoblastic leukaemia

Energy metabolism as the hub of advanced non-small cell lung cancer management: a comprehensive view in the framework of predictive, preventive, and personalized medicine

Targeting piRNA‐137463 Inhibits Tumor Progression and Boosts Sensitivity to Immune Checkpoint Blockade via De Novo Cholesterol Biosynthesis in Lung Adenocarcinoma

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