NEDD4 degrades TUSC2 to promote glioblastoma progression

Rimkus, Tadas; Arrigo, Austin; Zhu, Dongqin; Carpenter, Richard L.; Sirkisoon, Sherona; Doheny, Daniel; Regua, Angelina T.; Wong, Grace Lai Hung; Manore, Sara G.; Wagner, Calvin J.; Lin, Hui-Kuan; Jin, Guangxu; Ruiz, Jimmy; Chan, Michael D.; Debinski, Waldemar; Lo, Hui-Wen

doi:10.1016/j.canlet.2022.01.029

Cited by 6 publications

(12 citation statements)

References 48 publications

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“…We recently reported that poly-ubiquitination of TUSC2-K71 significantly decreases TUSC2 protein stability. Conversely, we found that point mutation of this TUSC2 residue (TUSC2-K71R) decreased TUSC2 poly-ubiquitination, and results in enhanced TUSC2 protein stability, indicating that TUSC2 protein stability is, in part, regulated through TUSC2-K71 polyubiquitination and subsequent TUSC2 proteasomal degradation [11].…”

Section: Introductionmentioning

confidence: 74%

“…Translation of TUSC2 mRNA produces a 110 amino acid protein consisting of multiple functional domains including a myristoylation motif (1-9 aa), myristoyl binding motif (45-110 aa), and an EF-hand calcium-binding motif (54-66 aa) [1,9,10]. Two post-translational modifications (PTMs) are frequently found on TUSC2, including N-terminal myristoylation and poly-ubiquitination of TUSC2 lysine residues K71, K84, and K93 [9,11]. TUSC2 N-terminal myristoylation covalently adds a 14-carbon myristoyl group to the N-terminal glycine residue (G2) during protein translation [9,12].…”

Section: Introductionmentioning

confidence: 99%

“…Proteins are most commonly marked for proteasomal degradation via protein polyubiquitination [16]. TUSC2 is poly-ubiquitinated on lysine residues K71, K84, and K93 in glioblastoma (GBM) [11]. We recently reported that poly-ubiquitination of TUSC2-K71 significantly decreases TUSC2 protein stability.…”

Section: Introductionmentioning

confidence: 99%

“…Recent discoveries determined that TUSC2 has multiple roles in overall normal cellular homeostasis, though the mechanisms of how TUSC2 regulates normal cellular functions remain unclear. Additionally, TUSC2 loss is studied in multiple cancers, including lung, breast, thyroid, ovarian, mesothelioma, gliomas, and other cancer types [9,11,[17][18][19][20]. This review will focus on the known functions of TUSC2 in normal tissues and the tumor suppressive functions of TUSC2 in multiple cancer types, as well as efforts in developing anti-cancer therapies that focus on restoring or sustaining TUSC2 expression.…”

Section: Introductionmentioning

confidence: 99%

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Tumor Suppressor Candidate 2 (TUSC2): Discovery, Functions, and Cancer Therapy

Arrigo

Regua

Najjar

et al. 2023

Cancers

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Tumor Suppressor Candidate 2 (TUSC2) was first discovered as a potential tumor suppressor gene residing in the frequently deleted 3p21.3 chromosomal region. Since its discovery, TUSC2 has been found to play vital roles in normal immune function, and TUSC2 loss is associated with the development of autoimmune diseases as well as impaired responses within the innate immune system. TUSC2 also plays a vital role in regulating normal cellular mitochondrial calcium movement and homeostasis. Moreover, TUSC2 serves as an important factor in premature aging. In addition to TUSC2′s normal cellular functions, TUSC2 has been studied as a tumor suppressor gene that is frequently deleted or lost in a multitude of cancers, including glioma, sarcoma, and cancers of the lung, breast, ovaries, and thyroid. TUSC2 is frequently lost in cancer due to somatic deletion within the 3p21.3 region, transcriptional inactivation via TUSC2 promoter methylation, post-transcriptional regulation via microRNAs, and post-translational regulation via polyubiquitination and proteasomal degradation. Additionally, restoration of TUSC2 expression promotes tumor suppression, eventuating in decreased cell proliferation, stemness, and tumor growth, as well as increased apoptosis. Consequently, TUSC2 gene therapy has been tested in patients with non-small cell lung cancer. This review will focus on the current understanding of TUSC2 functions in both normal and cancerous tissues, mechanisms of TUSC2 loss, TUSC2 cancer therapeutics, open questions, and future directions.

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Section: Introductionmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Tumor Suppressor Candidate 2 (TUSC2): Discovery, Functions, and Cancer Therapy

Arrigo

Regua

Najjar

et al. 2023

Cancers

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“…For instance, MYH9-mediated ubiquitination of GSK-3β promotes malignant progression and chemoresistance in glioma ( Que et al, 2022 ). The degradation of TUSC2 induced by NEDD4 facilitates glioblastoma progression ( Rimkus et al, 2022 ). PARK2, frequently mutated in glioma, acts as a tumor suppressor by boosting ubiquitination-dependent degradation of β-catenin, which results in attenuation of Wnt signaling ( Veeriah et al, 2010 ; Lin et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Characterization of a Novel E3-Related Gene Signature With Implications in Prognosis and Immunotherapy of Low-Grade Gliomas

et al. 2022

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Gliomas, a type of primary brain tumor, have emerged as a threat to global mortality due to their high heterogeneity and mortality. A low-grade glioma (LGG), although less aggressive compared with glioblastoma, still exhibits high recurrence and malignant progression. Ubiquitination is one of the most important posttranslational modifications that contribute to carcinogenesis and cancer recurrence. E3-related genes (E3RGs) play essential roles in the process of ubiquitination. Yet, the biological function and clinical significance of E3RGs in LGGs need further exploration. In this study, differentially expressed genes (DEGs) were screened by three differential expression analyses of LGG samples from The Cancer Genome Atlas (TCGA) database. DEGs with prognostic significance were selected by the univariate Cox regression analysis and log-rank statistical test. The LASSO-COX method was performed to identify an E3-related prognostic signature consisting of seven genes AURKA, PCGF2, MAP3K1, TRIM34, PRKN, TLE3, and TRIM17. The Chinese Glioma Genome Atlas (CGGA) dataset was used as the validation cohort. Kaplan–Meier survival analysis showed that LGG patients in the low-risk group had significantly higher overall survival time than those in the high-risk group in both TCGA and CGGA cohorts. Furthermore, multivariate Cox regression analysis revealed that the E3RG signature could be used as an independent prognostic factor. A nomogram based on the E3RG signature was then established and provided the prediction of the 1-, 3-, and 5-year survival probability of patients with LGGs. Moreover, DEGs were analyzed based on the risk signature, on which function analyses were performed. GO and KEGG analyses uncovered gene enrichment in extracellular matrix–related functions and immune-related biological processes in the high-risk group. GSEA revealed high enrichment in pathways that promote tumorigenesis and progression in the high-risk group. Furthermore, ESTIMATE algorithm analysis showed a significant difference in immune and stroma activity between high- and low-risk groups. Positive correlations between the risk signature and the tumor microenvironment immune cell infiltration and immune checkpoint molecules were also observed, implying that patients with the high-risk score may have better responses to immunotherapy. Overall, our findings might provide potential diagnostic and prognostic markers for LGG patients and offer meaningful insight for individualized treatment.

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