USP41 promotes breast cancer via regulating RACK1

Huang, Meiling; Xiao, Jingjing; Yan, Changjiao; Wang, Ting; Ling, Rui

doi:10.21037/atm-21-4921

Cited by 4 publications

(6 citation statements)

References 41 publications

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“…Three DRGs (PRSS2, SPPL2C and RHBDL1) were identified as protective factors and two DRGs (USP41 and ABHD12) were identified as risky factors for BRCA. In vitro experiments revealed that USP41 and ABHD12 play an essential role in breast cancer progression, which was consistent with the results of our functional assays ( 23 , 24 ). Elucidating the detailed regulatory mechanisms of USP41 and ABHD12 may help to further understand their roles in breast cancer.…”

Section: Discussionsupporting

confidence: 91%

A degradome-based prognostic signature that correlates with immune infiltration and tumor mutation burden in breast cancer

Luo

Chen

et al. 2023

Front. Immunol.

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IntroductionFemale breast cancer is the most common malignancy worldwide, with a high disease burden. The degradome is the most abundant class of cellular enzymes that play an essential role in regulating cellular activity. Dysregulation of the degradome may disrupt cellular homeostasis and trigger carcinogenesis. Thus we attempted to understand the prognostic role of degradome in breast cancer by means of establishing a prognostic signature based on degradome-related genes (DRGs) and assessed its clinical utility in multiple dimensions.MethodsA total of 625 DRGs were obtained for analysis. Transcriptome data and clinical information of patients with breast cancer from TCGA-BRCA, METABRIC and GSE96058 were collected. NetworkAnalyst and cBioPortal were also utilized for analysis. LASSO regression analysis was employed to construct the degradome signature. Investigations of the degradome signature concerning clinical association, functional characterization, mutation landscape, immune infiltration, immune checkpoint expression and drug priority were orchestrated. Cell phenotype assays including colony formation, CCK8, transwell and wound healing were conducted in MCF-7 and MDA-MB-435S breast cancer cell lines, respectively.ResultsA 10-gene signature was developed and verified as an independent prognostic predictor combined with other clinicopathological parameters in breast cancer. The prognostic nomogram based on risk score (calculated based on the degradome signature) showed favourable capability in survival prediction and advantage in clinical benefit. High risk scores were associated with a higher degree of clinicopathological events (T4 stage and HER2-positive) and mutation frequency. Regulation of toll-like receptors and several cell cycle promoting activities were upregulated in the high-risk group. PIK3CA and TP53 mutations were dominant in the low- and high-risk groups, respectively. A significantly positive correlation was observed between the risk score and tumor mutation burden. The infiltration levels of immune cells and the expressions of immune checkpoints were significantly influenced by the risk score. Additionally, the degradome signature adequately predicted the survival of patients undergoing endocrinotherapy or radiotherapy. Patients in the low-risk group may achieve complete response after the first round of chemotherapy with cyclophosphamide and docetaxel, whereas patients in the high-risk group may benefit from 5-flfluorouracil. Several regulators of the PI3K/AKT/mTOR signaling pathway and the CDK family/PARP family were identified as potential molecular targets in the low- and high-risk groups, respectively. In vitro experiments further revealed that the knockdown of ABHD12 and USP41 significantly inhibit the proliferation, invasion and migration of breast cancer cells.ConclusionMultidimensional evaluation verified the clinical utility of the degradome signature in predicting prognosis, risk stratification and guiding treatment for patients with breast cancer.

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Section: Discussionsupporting

confidence: 91%

A degradome-based prognostic signature that correlates with immune infiltration and tumor mutation burden in breast cancer

Luo

Chen

et al. 2023

Front. Immunol.

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“…Finally, since USP41 is not a second ISG15 protease, we aimed at characterizing which Ubl it controls in vivo. Despite a few reports stating that it is a deubiquitinating enzyme (DUB) 35,36 , we found that USP41 can regulate the Ubl FAT10 (HLA-F adjacent transcript 10), which presents similar features as ISG15. For instance, FAT10 structure is comprised of two ubiquitin-like molecules 37 , and its expression is induced by pro-inflammatory cytokines such as IFN-γ and tumor necrosis factor (TNF), while it is mostly restricted to cell types of the immune system 38 .…”

Section: Introductioncontrasting

confidence: 82%

Mechanisms of USP18 deISGylation revealed by comparative analysis with its human paralog USP41

Bonacci,

Bolhuis,

Brown

et al. 2024

Preprint

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The ubiquitin-like protein ISG15 (interferon-stimulatedgene15) regulates the host response to bacterial and viral infections through its conjugation to proteins (ISGylation) following interferon production. ISGylation is antagonized by the highly specific cysteine protease USP18, which is the major deISGylating enzyme. However, mechanisms underlying USP18’s extraordinary specificity towards ISG15 remains elusive. Here, we show that USP18 interacts with its paralog USP41, whose catalytic domain shares 97% identity with USP18. However, USP41 does not act as a deISGylase, which led us to perform a comparative analysis to decipher the basis for this difference, revealing molecular determinants of USP18’s specificity towards ISG15. We found that USP18 C-terminus, as well as a conserved Leucine at position 198, are essential for its enzymatic activity and likely act as functional surfaces based on AlphaFold predictions. Finally, we propose that USP41 antagonizes conjugation of the understudied ubiquitin-like protein FAT10 (HLA-Fadjacent transcript10) from substrates in a catalytic-independent manner. Altogether, our results offer new insights into USP18’s specificity towards ISG15, while identifying USP41 as a negative regulator of FAT10 conjugation.

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“…Previously, Huang et al identified the RACK1 as a novel protein interacting with USP41 through CoIP-MS analysis and indicated the promotion of migration via USP41-induced RACK1 upregulation [ 25 ]. Since function of RACK1 is diverse and extensive in breast cancer, they mentioned that the investigation of the roles of USP41-mediated RACK1 in cancer cell migration are necessary.…”

Section: Discussionmentioning

confidence: 99%

“…Since function of RACK1 is diverse and extensive in breast cancer, they mentioned that the investigation of the roles of USP41-mediated RACK1 in cancer cell migration are necessary. In addition, they did not examine the EMT-regulated proteins by USP41 knockdown or overexpression [ 25 ]. In our study, knockdown or overexpression of USP41 induced the downregulation or upregulation of Snail protein expression in breast cancer cells, respectively ( Figure 4 A–C).…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have analyzed overall survival of cancer patients according to expression of USP41 based on The Cancer Genome Atlas (TCGA) database and suggested USP41 as marker predicting prognosis especially in invasive breast cancer and lung cancer [ 23 , 24 ]. Even though some researchers have reported that USP41 promotes cancer cell migration and proliferation [ 25 , 26 ], the underlying specific mechanism to cancer migration and EMT is still unclear.…”

Section: Introductionmentioning

confidence: 99%

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USP41 Enhances Epithelial–Mesenchymal Transition of Breast Cancer Cells through Snail Stabilization

Yoon

Seo

Woo

et al. 2023

IJMS

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Ubiquitination, one of many post-translational modifications, causes proteasome-mediated protein degradation by attaching ubiquitin to target proteins. Multiple deubiquitinases inhibit the ubiquitination pathway by removing the ubiquitin chain from protein, thus contributing to the stabilization of substrates. USP41 contributes to invasion, apoptosis and drug resistance in breast and lung cancer cells. However, the detailed mechanism and role of USP41 in breast cancer have not been elucidated. USP41 was overexpressed and showed poor prognosis according to the aggressive phenotype of breast cancer cells. Knockdown of USP41 inhibited migration and growth of breast cancer cells, whereas overexpression of USP41 increased cell growth and migration. In addition, depletion of USP41 downregulated Snail protein expression, an epithelial–mesenchymal transition marker, but not mRNA expression. Furthermore, USP41 interacted with and inhibited ubiquitination of Snail, resulting in the increase in Snail stabilization. Therefore, these data demonstrated that USP41 increases migration of breast cancer cells through Snail stabilization.

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USP41 promotes breast cancer via regulating RACK1

Cited by 4 publications

References 41 publications

A degradome-based prognostic signature that correlates with immune infiltration and tumor mutation burden in breast cancer

A degradome-based prognostic signature that correlates with immune infiltration and tumor mutation burden in breast cancer

Mechanisms of USP18 deISGylation revealed by comparative analysis with its human paralog USP41

USP41 Enhances Epithelial–Mesenchymal Transition of Breast Cancer Cells through Snail Stabilization

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