USP21 deubiquitinase promotes pancreas cancer cell stemness via Wnt pathway activation

Hou, Pingping; Ma, Xingdi; Zhang, Qiang; Wu, Chang-Jiun; Liao, Wenting; Li, Jun; Wang, Huamin; Zhao, Jun; Zhou, Xin; Guan, Carolyn; Ackroyd, Jeffery; Jiang, Shan; Zhang, Jianhua; Spring, Denise J.; Wang, Y. Alan; DePinho, Ronald A.

doi:10.1101/gad.326314.119

Cited by 76 publications

(79 citation statements)

References 38 publications

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“…USP21 ampli cation was also observed in other cancer types (Fig. 4a), which is consistent with previous studies that USP21 regulates cell proliferation and metastasis in colorectal cancer and pancreas cancer (Yun et al 2020;Hou et al 2019). Next, we con rmed the expression levels of PD-L1 and USP21 in LUSC and found that upregulated expression of PD-L1 accounted for 80% (395 of 494) of LUSC samples, while USP21 accounted for 76% (375 of 494) of LUSC samples (Fig.…”

Section: Usp21 Functions As a Pd-l1 Dubsupporting

confidence: 90%

Deubiquitination and Stabilization of PD-L1 by USP21

Yang

Yan

et al. 2021

Preprint

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Background: The immunotherapy for different types of cancers that targeting programmed death protein-1 (PD-1) and programmed death ligand-1 (PD-L1) has highlighted the importance of suppressing specific T cell responses. Recently, several studies have shown that the expression level of PD-L1 in tumor cells is positively correlated with tumor metastasis as well as recurrence rate. The potent effects of post-translational modifications (PTMs) for PD-L1, such as ubiquitination, glycosylation, phosphorylation and palmitoylation, have been reported to be related to immunosuppression. However, the regulation of PD-L1 degradation in cancers is still not well understood. In this paper, we mainly investigate the deubiquitination regulation of PD-L1. Methods: The protein levels of PD-L1 and USP21 were detected by Immunoblotting and immunohistochemistry. The interaction between PD-L1 and USP21 was determined by co-immunoprecipitation. The deubiquitination of PD-L1 was determined by in vitro deubiquitination assay. The deubiquitination sites of PD-L1 were identified by mass spectrometry analysis. The expression of mRNA in target tissues was presented by bioinformatics analysis.Results: Overexpression of USP21 significantly increased PD-L1 abundance and knockdown of USP21 induced degradation of PD-L1. In vitro deubiquitination assay showed that USP21-WT reduced polyubiquitin chains from PD-L1 while USP21-C221A did not. Furthermore, five lysines in intracellular segment of PD-L1 are potential deubiquitin sites and cancer-derived mutations of PD-L1 in Asp276 have the ability to enhance the deubiquitination of PD-L1 mediated by USP21. Finally, we found that USP21 is the frequently amplified deubiquitinase in lung cancer, especially in lung squamous cell carcinoma, and its amplification co-occurs with the upregulation of PD-L1 levels. Moreover, IHC analysis showed stronger staining of PD-L1 and USP21 in lung cancer samples than adjacent tissues. Conclusion: We identified USP21 as a novel deubiquitinase of PD-L1. Hopefully, targeting PD-L1 by inhibiting USP21 might be a potentially novel strategy for the treatment of lung cancer.

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Section: Usp21 Functions As a Pd-l1 Dubsupporting

confidence: 90%

Deubiquitination and Stabilization of PD-L1 by USP21

Yang

Yan

et al. 2021

Preprint

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“…Antibody information is listed in Supplementary Table 2. Western blot, IP, co-IP, IHC and IF staining were performed following standard protocols as previously described (5,51). Mass spectrometry analysis of proteins pulled down by FLAG-tagged HDAC5 were performed by Proteomics Core Facility at The University of Texas Southwestern Medical Center.…”

Section: Antibodies Western Blot Ip Co-ip/ms Ihc If and Elisamentioning

confidence: 99%

Tumor Microenvironment Remodeling Enables Bypass of Oncogenic KRAS Dependency in Pancreatic Cancer

et al. 2020

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Oncogenic KRAS (KRAS*) is a key tumor maintenance gene in pancreatic ductal adenocarcinoma (PDAC), motivating pharmacological targeting of KRAS* and its effectors. Here, we explored mechanisms involving the tumor microenvironment (TME) as a potential basis for resistance to targeting KRAS*. Using the inducible Kras G12D p53 null (iKPC) PDAC mouse model, gain-offunction screens of epigenetic regulators identified HDAC5 as the top hit enabling KRAS* independent tumor growth. HDAC5-driven escaper tumors showed a prominent neutrophil-tomacrophage switch relative to KRAS*-driven tumors. Mechanistically, HDAC5 represses Socs3, a negative regulator of chemokine CCL2, resulting in increased CCL2 which recruits CCR2 + macrophages. Correspondingly, enforced Ccl2 promotes macrophage recruitment into the TME and enables tumor recurrence following KRAS* extinction. These tumor-associated macrophages (TAMs) in turn provide cancer cell with trophic support including TGFβ to enable KRAS* bypass in a Smad4-dependent manner. Our work uncovers a KRAS* resistance mechanism involving immune cell remodeling of the PDAC TME.

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“…USP21 promotes cell proliferation, tumor progression, and colony formation, and enhances cancer stem cell self-renewal. USP21 stabilizes the Wnt (Wingless-related integration site) pathway transcription factor 7 (TCF7) to activate gene expression in the Wnt network [ 55 ].…”

Section: Resultsmentioning

confidence: 99%

Genomic Analysis of Localized High-Risk Prostate Cancer Circulating Tumor Cells at the Single-Cell Level

Rangel‐Pozzo

Liu

Wajnberg

et al. 2020

Cells

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Accurate risk classification of men with localized high-risk prostate cancer directly affects treatment management decisions and patient outcomes. A wide range of risk assessments and classifications are available. However, each one has significant limitations to distinguish between indolent and aggressive prostate cancers. Circulating tumor cells (CTCs) may provide an alternate additional source, beyond tissue biopsies, to enable individual patient-specific clinical assessment, simply because CTCs can reveal both tumor-derived and germline-specific genetic information more precisely than that gained from a single diagnostic biopsy. In this study, we combined a filtration-based CTC isolation technology with prostate cancer CTC immunophenotyping to identify prostate cancer CTCs. Next, we performed 3-D telomere profiling prior to laser microdissection and single-cell whole-exome sequencing (WES) of 21 CTCs and 4 lymphocytes derived from 10 localized high-risk prostate cancer patient samples. Localized high-risk prostate cancer patient CTCs present a high number of telomere signals with lower signal intensities (short telomeres). To capture the genetic diversity/heterogeneity of high-risk prostate cancer CTCs, we carried out whole-exome sequencing. We identified 202,241 single nucleotide variants (SNVs) and 137,407 insertion-deletions (indels), where less than 10% of these genetic variations were within coding regions. The genetic variation (SNVs + indels) and copy number alteration (CNAs) profiles were highly heterogeneous and intra-patient CTC variation was observed. The pathway enrichment analysis showed the presence of genetic variation in nine telomere maintenance pathways (patients 3, 5, 6, and 7), including an important gene for telomere maintenance called telomeric repeat-binding factor 2 (TRF2). Using the PharmGKB database, we identified nine genetic variations associated with response to docetaxel. A total of 48 SNVs can affect drug response for 24 known cancer drugs. Gene Set Enrichment Analysis (GSEA) (patients 1, 3, 6, and 8) identified the presence of CNAs in 11 different pathways, including the DNA damage repair (DDR) pathway. In conclusion, single-cell approaches (WES and 3-D telomere profiling) showed to be useful in unmasking CTC heterogeneity. DDR pathway mutations have been well-established as a target pathway for cancer therapy. However, the frequent CNA amplifications found in localized high-risk patients may play critical roles in the therapeutic resistance in prostate cancer.

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USP21 deubiquitinase promotes pancreas cancer cell stemness via Wnt pathway activation

Cited by 76 publications

References 38 publications

Deubiquitination and Stabilization of PD-L1 by USP21

Deubiquitination and Stabilization of PD-L1 by USP21

Tumor Microenvironment Remodeling Enables Bypass of Oncogenic KRAS Dependency in Pancreatic Cancer

Genomic Analysis of Localized High-Risk Prostate Cancer Circulating Tumor Cells at the Single-Cell Level

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