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Protein ubiquitination plays a pivotal role in protein homeostasis. Ubiquitination may regulate the stability, activity, protein–protein interaction, and localization of a protein. Ubiquitination is subject to regulation by two groups of counteracting enzymes, the E3 ubiquitin ligases and deubiquitinases. Consistently, deubiquitinases are involved in essentially all biological processes. OTUB1, an OTU-family deubiquitinase, is a critical regulator of development, cancer, DNA damage response, and immune response. OTUB1 antagonizes the ubiquitination of a wide-spectrum of proteins through at least two different mechanisms. Besides direct deubiquitination, OTUB1 can also inhibit ubiquitination by non-canonically blocking ubiquitin transfer from certain ubiquitin-conjugases (E2). In this review, we start with a general background of protein ubiquitination and deubiquitination. Next, we introduce the basic characteristics of OTUB1 and then elaborate on the updated biological functions of OTUB1. Afterwards, we discuss potential mechanisms underlying the versatility and specificity of OTUB1 functions. In the end, we discuss the perspective that OTUB1 can be a potential therapeutic target for cancer.

Higher demand for nutrients including glucose is characteristic of cancer. "Starving cancer" has been pursued to curb tumor progression. An intriguing regime is to inhibit glucose transporter GLUT1 in cancer cells. In addition, during cancer progression, cancer cells may suffer from insufficient glucose supply. Yet, cancer cells can somehow tolerate glucose starvation. Uncovering the underlying mechanisms shall shed insight into cancer progression and benefit cancer therapy. TFE3 is a transcription factor known to activate autophagic genes. Physiological TFE3 activity is regulated by phosphorylationtriggered translocation responsive to nutrient status. We recently reported TFE3 constitutively localizes to the cell nucleus and promotes cell proliferation in kidney cancer even under nutrient replete condition. It remains unclear whether and how TFE3 responds to glucose starvation. In this study, we show TFE3 promotes kidney cancer cell resistance to glucose starvation by exposing cells to physiologically relevant glucose concentration. We find glucose starvation triggers TFE3 protein stabilization through increasing its O-GlcNAcylation. Furthermore, through an unbiased functional genomic study, we identify SLC36A1, a lysosomal amino acid transporter, as a TFE3 target gene sensitive to TFE3 protein level. We find SLC36A1 is overexpressed in kidney cancer, which promotes mTOR activity and kidney cancer cell proliferation. Importantly, SLC36A1 level is induced by glucose starvation through TFE3, which enhances cellular resistance to glucose starvation. Suppressing TFE3 or SLC36A1 significantly increases cellular sensitivity to GLUT1 inhibitor in kidney cancer cells. Collectively, we uncover a functional TFE3–SLC36A1 axis that responds to glucose starvation and enhances starvation tolerance in kidney cancer. [ABSTRACT FROM AUTHOR]

Prostate cancer is a leading cause of cancer-related mortality in males. Dysregulation of RNA adenine N-6 methylation (m6A) contributes to cancer malignancy. m6A on mRNA may affect mRNA splicing, turnover, transportation, and translation. m6A exerts these effects, at least partly, through dedicated m6A reader proteins, including YTH domain--containing family protein 2 (YTHDF2). YTHDF2 is necessary for development while its dysregulation is seen in various cancers, including prostate cancer. However, the mechanism underlying the dysregulation and function of YTHDF2 in cancer remains elusive. Here, we find that the deubiquitinase OUT domain--containing ubiquitin aldehyde-binding protein 1 (OTUB1) increases YTHDF2 protein stability by inhibiting its ubiquitination. With in vivo and in vitro ubiquitination assays, OTUB1 is shown to block ubiquitin transfer to YTHDF2 independent of its deubiquitinase activity. Furthermore, analysis of functional transcriptomic data and m6A-sequencing data identifies PRSS8 as a potential tumor suppressor gene. OTUB1 and YTHDF2 decrease mRNA and protein levels of PRSS8, which is a trypsinlike serine protease. Mechanistically, YTHDF2 binds PRSS8 mRNA and promotes its degradation in an m6A-dependent manner. Further functional study on cellular and mouse models reveals PRSS8 is a critical downstream effector of the OTUB1--YTHDF2 axis in prostate cancer. We find in prostate cancer cells, PRSS8 decreases nuclear β-catenin level through E-cadherin, which is independent of its protease activity. Collectively, our study uncovers a key regulator of YTHDF2 protein stability and establishes a functional OTUB1-- YTHDF2--PRSS8 axis in prostate cancer. [ABSTRACT FROM AUTHOR]

Liver cancer is notoriously refractory to conventional therapeutics. Tumor progression is governed by the interplay between tumor-promoting genes and tumor-suppressor genes. BRD4, an acetyl lysine-binding protein, is overexpressed in many cancer types, which promotes activation of a pro-tumor gene network. But the underlying mechanism for BRD4 overexpression remains incompletely understood. In addition, understanding the regulatory mechanism of BRD4 protein level will shed insight into BRD4-targeting therapeutics. In this study, we investigated the potential relation between BRD4 protein level and P53, the most frequently dysregulated tumor suppressor. By analyzing the TCGA datasets, we first identify a strong negative correlation between protein levels of P53 and BRD4 in liver cancer. Further investigation shows that P53 promotes BRD4 protein degradation. Mechanistically, P53 indirectly represses the transcription of USP1, a deubiquitinase, through the P21-RB1 axis. USP1 itself is also overexpressed in liver cancer and we show USP1 deubiquitinates BRD4 in vivo and in vitro, which increases BRD4 stability. With cell proliferation assays and xenograft model, we show the protumor role of USP1 is partially mediated by BRD4. With functional transcriptomic analysis, we find the USP1-BRD4 axis upholds expression of a group of cancer-related genes. In summary, we identify a functional P53-P21-RB1-USP1-BRD4 axis in liver cancer. [ABSTRACT FROM AUTHOR]