USP21 Regulates Hippo Pathway Activity by Mediating MARK Protein Turnover

Overview

Journal Oncotarget

Specialty Oncology

Date 2017 Oct 4

PMID 28969054

Citations 14

Authors

Hung Thanh Nguyen

Jan-Michael Kugler

Anand C Loya

Stephen M Cohen

Affiliations

Soon will be listed here.

Abstract

The Hippo pathway, which acts to repress the activity of YAP and TAZ trancriptional co-activators, serve as a barrier for oncogenic transformation. Unlike other oncoproteins, YAP and TAZ are rarely activated by mutations or amplified in cancer. However, elevated YAP/TAZ activity is frequently observed in cancer and often correlates with worse survival. The activity and stability of Hippo pathway components, including YAP/TAZ, AMOT and LATS1/2, are regulated by ubiquitin-mediated protein degradation. Aberrant expression of ubiquitin ligase complexes that regulate the turnover of Hippo components and deubiquitylating enzymes that counteract these ubiquitin ligases have been implicated in human cancer. Here we identify the USP21 deubiquitylating enzyme as a novel regulator of Hippo pathway activity. We provide evidence that USP21 regulates YAP/TAZ activity by controlling the stability of MARK kinases, which promote Hippo signaling. Low expression of USP21 in early stage renal clear cell carcinoma suggests that USP21 may be a useful biomarker.

Citing Articles

USP21-mediated G3BP1 stabilization accelerates proliferation and metastasis of esophageal squamous cell carcinoma via activating Wnt/β-Catenin signaling.

Guo J, Zhao Y, Sui H, Liu L, Liu F, Yang L Oncogenesis. 2024; 13(1):23.

PMID: 38906857 PMC: 11192907. DOI: 10.1038/s41389-024-00524-3.

Deubiquitylating Enzymes in Cancer and Immunity.

Ren J, Yu P, Liu S, Li R, Niu X, Chen Y Adv Sci (Weinh). 2023; 10(36):e2303807.

PMID: 37888853 PMC: 10754134. DOI: 10.1002/advs.202303807.

Synergistic effect of YOD1 and USP21 on the Hippo signaling pathway.

Park S, Baek K Cancer Cell Int. 2023; 23(1):209.

PMID: 37743467 PMC: 10518088. DOI: 10.1186/s12935-023-03078-3.

Insights Into the Properties, Biological Functions, and Regulation of USP21.

An T, Lu Y, Yan X, Hou J Front Pharmacol. 2022; 13:944089.

PMID: 35846989 PMC: 9279671. DOI: 10.3389/fphar.2022.944089.

Deubiquitination and Stabilization of PD-L1 by USP21.

Yang S, Yan H, Wu Y, Shan B, Zhou D, Liu X Am J Transl Res. 2021; 13(11):12763-12774.

PMID: 34956491 PMC: 8661224.

References

Voorhoeve P, le Sage C, Schrier M, Gillis A, Stoop H, Nagel R . A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors. Cell. 2006; 124(6):1169-81. DOI: 10.1016/j.cell.2006.02.037. View

Fullenkamp C, Hall S, Jaber O, Pakalniskis B, Savage E, Savage J . TAZ and YAP are frequently activated oncoproteins in sarcomas. Oncotarget. 2016; 7(21):30094-108. PMC: 5058666. DOI: 10.18632/oncotarget.8979. View

Salah Z, Melino G, Aqeilan R . Negative regulation of the Hippo pathway by E3 ubiquitin ligase ITCH is sufficient to promote tumorigenicity. Cancer Res. 2011; 71(5):2010-20. DOI: 10.1158/0008-5472.CAN-10-3516. View

Xu G, Tan X, Wang H, Sun W, Shi Y, Burlingame S . Ubiquitin-specific peptidase 21 inhibits tumor necrosis factor alpha-induced nuclear factor kappaB activation via binding to and deubiquitinating receptor-interacting protein 1. J Biol Chem. 2009; 285(2):969-78. PMC: 2801298. DOI: 10.1074/jbc.M109.042689. View

Sun Z, Xu R, Li X, Ren W, Ou C, Wang Q . Prognostic Value of Yes-Associated Protein 1 (YAP1) in Various Cancers: A Meta-Analysis. PLoS One. 2015; 10(8):e0135119. PMC: 4532485. DOI: 10.1371/journal.pone.0135119. View

Wang L, Shi S, Guo Z, Zhang X, Han S, Yang A . Overexpression of YAP and TAZ is an independent predictor of prognosis in colorectal cancer and related to the proliferation and metastasis of colon cancer cells. PLoS One. 2013; 8(6):e65539. PMC: 3677905. DOI: 10.1371/journal.pone.0065539. View

Sowa M, Bennett E, Gygi S, Harper J . Defining the human deubiquitinating enzyme interaction landscape. Cell. 2009; 138(2):389-403. PMC: 2716422. DOI: 10.1016/j.cell.2009.04.042. View

Asthagiri A, Parry D, Butman J, Kim H, Tsilou E, Zhuang Z . Neurofibromatosis type 2. Lancet. 2009; 373(9679):1974-86. PMC: 4748851. DOI: 10.1016/S0140-6736(09)60259-2. View

Nilsson M, Meza-Zepeda L, Mertens F, Forus A, Myklebost O, Mandahl N . Amplification of chromosome 1 sequences in lipomatous tumors and other sarcomas. Int J Cancer. 2004; 109(3):363-9. DOI: 10.1002/ijc.11716. View

10.

Meng Z, Moroishi T, Guan K . Mechanisms of Hippo pathway regulation. Genes Dev. 2016; 30(1):1-17. PMC: 4701972. DOI: 10.1101/gad.274027.115. View

11.

Allemandou F, Nussberger J, Brunner H, Brakch N . Rapid Site-Directed Mutagenesis Using Two-PCR-Generated DNA Fragments Reproducing the Plasmid Template. J Biomed Biotechnol. 2003; 2003(3):202-207. PMC: 400210. DOI: 10.1155/S1110724303209141. View

12.

Lignitto L, Arcella A, Sepe M, Rinaldi L, Delle Donne R, Gallo A . Proteolysis of MOB1 by the ubiquitin ligase praja2 attenuates Hippo signalling and supports glioblastoma growth. Nat Commun. 2013; 4:1822. PMC: 3674242. DOI: 10.1038/ncomms2791. View

13.

Kim M, Kim J, Hong H, Lee S, Lee J, Jung E . Actin remodeling confers BRAF inhibitor resistance to melanoma cells through YAP/TAZ activation. EMBO J. 2015; 35(5):462-78. PMC: 4772854. DOI: 10.15252/embj.201592081. View

14.

Lin L, Sabnis A, Chan E, Olivas V, Cade L, Pazarentzos E . The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies. Nat Genet. 2015; 47(3):250-6. PMC: 4930244. DOI: 10.1038/ng.3218. View

15.

Mohseni M, Sun J, Lau A, Curtis S, Goldsmith J, Fox V . A genetic screen identifies an LKB1-MARK signalling axis controlling the Hippo-YAP pathway. Nat Cell Biol. 2013; 16(1):108-17. PMC: 4159053. DOI: 10.1038/ncb2884. View

16.

Richter A, Pfeifer G, Dammann R . The RASSF proteins in cancer; from epigenetic silencing to functional characterization. Biochim Biophys Acta. 2009; 1796(2):114-28. DOI: 10.1016/j.bbcan.2009.03.004. View

17.

Hong X, Nguyen H, Chen Q, Zhang R, Hagman Z, Voorhoeve P . Opposing activities of the Ras and Hippo pathways converge on regulation of YAP protein turnover. EMBO J. 2014; 33(21):2447-57. PMC: 4283404. DOI: 10.15252/embj.201489385. View

18.

Zender L, Spector M, Xue W, Flemming P, Cordon-Cardo C, Silke J . Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell. 2006; 125(7):1253-67. PMC: 3026384. DOI: 10.1016/j.cell.2006.05.030. View

19.

Bai H, Gayyed M, Lam-Himlin D, Klein A, Nayar S, Xu Y . Expression of Yes-associated protein modulates Survivin expression in primary liver malignancies. Hum Pathol. 2012; 43(9):1376-85. PMC: 3384990. DOI: 10.1016/j.humpath.2011.12.001. View

20.

Chagtai T, Zill C, Dainese L, Wegert J, Savola S, Popov S . Gain of 1q As a Prognostic Biomarker in Wilms Tumors (WTs) Treated With Preoperative Chemotherapy in the International Society of Paediatric Oncology (SIOP) WT 2001 Trial: A SIOP Renal Tumours Biology Consortium Study. J Clin Oncol. 2016; 34(26):3195-203. PMC: 5505170. DOI: 10.1200/JCO.2015.66.0001. View