Yes-associated protein (YAP) is one of major key effectors of the Hippo pathway and the mechanism supporting abnormal YAP expression in Anaplastic thyroid carcinoma (ATC) remains to be characterized. Here, we identified ubiquitin carboxyl terminal hydrolase L3 (UCHL3) as a bona fide deubiquitylase of YAP in ATC. UCHL3 stabilized YAP in a deubiquitylation activity-dependent manner. UCHL3 depletion significantly decreased ATC progression, stem-like and metastasis, and increased cell sensitivity to chemotherapy. Depletion of UCHL3 decreased the YAP protein level and the expression of YAP/TEAD target genes in ATC. UCHL3 promoter analysis revealed that TEAD4, through which YAP bind to DNA, activated UCHL3 transcription by binding to the promoter of UCHL3. In general, our results demonstrated that UCHL3 plays a pivotal role in stabilizing YAP, which in turn facilitates tumorigenesis in ATC, suggesting that UCHL3 may prove to be a potential target for the treatment of ATC.

Anaplastic thyroid cancer (ATC) is one of the most lethal and aggressive human malignancies, with no effective treatment currently available. The Hippo tumor suppressor pathway is highly conserved in mammals and plays an important role in carcinogenesis. TAZ is one of major key effectors of the Hippo pathway. However, the mechanism supporting abnormal TAZ expression in ATC remains to be characterized. In the present study, we identified USP26, a DUB enzyme in the ubiquitin-specific proteases family, as a bona fide deubiquitylase of TAZ in ATC. USP26 was shown to interact with, deubiquitylate, and stabilize TAZ in a deubiquitylation activity-dependent manner. USP26 depletion significantly decreased ATC cell proliferation, migration, and invasion. The effects induced by USP26 depletion could be rescued by further TAZ overexpression. Depletion of USP26 decreased the TAZ protein level and the expression of TAZ/TEAD target genes in ATC, including CTGF, ANKRD1, and CYR61. In general, our findings establish a previously undocumented catalytic role for USP26 as a deubiquitinating enzyme of TAZ and provides a possible target for the therapy of ATC.

Background: Hepatocellular carcinoma (HCC) is an aggressive and heterogeneous disease characterized by high morbidity and mortality. The liver is the vital organ that participates in tyrosine catabolism, and abnormal tyrosine metabolism could cause various diseases, including HCC. Besides, the tumor immune microenvironment is involved in carcinogenesis and can influence the patients’ clinical outcomes. However, the potential role of tyrosine metabolism pattern and immune molecular signature is poorly understood in HCC.Methods: Gene expression, somatic mutations, copy number variation data, and clinicopathological information of HCC were downloaded from The Cancer Genome Atlas (TCGA) database. GSE14520 from the Gene Expression Omnibus (GEO) databases was used as a validation dataset. We performed unsupervised consensus clustering of tyrosine metabolism-related genes (TRGs) and classified patients into distinct molecular subtypes. We used ESTIMATE algorithms to evaluate the immune infiltration. We then applied LASSO Cox regression to establish the TRGs risk model and validated its predictive performance.Results: In this study, we first described the alterations of 42 TRGs in HCC cohorts and characterized the clinicopathological characteristics and tumor microenvironmental landscape of the two distinct subtypes. We then established a tyrosine metabolism-related scoring system and identified five TRGs, which were highly correlated with prognosis and representative of this gene set, namely METTL6, GSTZ1, ADH4, ADH1A, and LCMT1. Patients in the high-risk group had an inferior prognosis. Univariate and multivariate Cox proportional hazards regression analysis also showed that the tyrosine metabolism-related signature was an independent prognostic indicator. Besides, receiver operating characteristic curve (ROC) analysis demonstrated the predictive accuracy of the TRGs signature that could reliably predict 1-, 3-, and 5-year survival in both TCGA and GEO cohorts. We also got consistent results by performing clone formation and invasion analysis, and immunohistochemical (IHC) assays. Moreover, we also discovered that the TRGs signature was significantly associated with the different immune landscapes and therapeutic drug sensitivity.Conclusion: Our comprehensive analysis revealed the potential molecular signature and clinical utilities of TRGs in HCC. The model based on five TRGs can accurately predict the survival outcomes of HCC, improving our knowledge of TRGs in HCC and paving a new path for guiding risk stratification and treatment strategy development for HCC patients.

Breast cancer is the most commonly diagnosed malignant tumor among females. Estrogen receptor α (ERα) is initially expressed in 70% of breast cancers and is a well-known target of endocrine therapy for ERα-positive breast cancer. In the present study, we identified MINDY1, a member belongs to the motif interacting with Ubcontaining novel DUB family (MINDY), as a potential deubiquitylase of ERα in breast cancer. There was a positive correlation between ERα and MINDY1 protein levels in human breast cancer tissues. We found that high expression of MINDY1 was associated with poor prognosis. MINDY1 interacted with ERα, thereby mediating the deubiquitination of ERα and increased its stability in a deubiquitylation activity-dependent manner. MINDY1 depletion significantly decreased the ERα protein level and ERα signaling activity in breast cancer cells. Specifically, MINDY1 associated with the N-terminal of ERα via its catalytic domain, thus inhibiting K48-specific poly-ubiquitination process on ERα protein. In addition, MINDY1 depletion led to growth inhibition and cell cycle arrest of ERα-positive breast cancer cells. Finally, overexpression of ERα could rescue the MINDY1 depletion-induced growth inhibition both in vitro and in vivo, suggesting that MINDY1 promotes breast carcinogenesis through increasing ERα stability. Overall, our study proposed a novel post-translational mechanism of ERα in supporting breast cancer progression. Targeting the MINDY1 may prove to be a promising strategy for patients with ERα-positive breast cancer.

Breast cancer ranks first among female malignancies worldwide, and estrogen receptor-positive (ER+) breast cancer is the leading cause of cancer death in women. Abnormal oncogenic signaling has important effects on the development of breast cancer, such as ERα/ ESR1 (estrogen receptor alpha), PTEN (gene of phosphate and tension homology deleted on chromsome ten), NFκB(nuclear factor κB), and tumor protein p53 (p53 / TP53). SHARPIN is a ubiquitin-related protein that has important regulatory functions in inflammation control, immune organ development, and cancer development. SHARPIN is highly expressed in many cancers, especially in breast cancer. It plays an important role in controlling important carcinogenic pathways in breast cancer, such as p53 and ERα. This review emphasizes the functional role of SHARPIN and the recent advances in the molecular mechanisms by which SHARPIN regulates breast cancer development through ubiquitination.

Breast cancer is one of the most frequently diagnosed malignancies and a leading cause of cancer death among females. Multiple molecular alterations are observed in breast cancer. LncRNA transcripts were proved to play important roles in the biology of tumorigenesis. In this study, we aimed to identify lncRNA expression signature that can predict breast cancer patient survival. We developed a 10‐lncRNA signature‐based risk score which was used to separate patients into high‐risk and low‐risk groups. Patients in the low‐risk group had significantly better survival than those in the high‐risk group. Receiver operating characteristic analysis indicated that this signature exhibited excellent diagnostic efficiency for 1‐, 3‐ and 5‐year disease‐relapse events. Moreover, multivariate Cox regression analysis demonstrated that this 10‐lncRNA signature was an independent risk factor when adjusting for several clinical signatures such as age, tumour size and lymph node status. The prognostic value of risk scores was validated in the validation set. In addition, a nomogram was established and the calibration plots analysis indicated the good performance and clinical utility of the nomogram. In conclusion, our results demonstrated that this 10‐lncRNA signature effectively grouped patients at low and high risk of disease recurrence.