UBQLN4 is an ATM substrate that stabilizes the anti-apoptotic proteins BCL2A1 and BCL2L10 in mesothelioma

Our plain-English summary of UBQLN4 is an ATM substrate that stabilizes the anti-apoptotic proteins BCL2A1 and BCL2L10 in mesothelioma, by F. Liu, R. Pan, H. Ding, et al (Molecular Oncology, 2021).

The study

• Authors: F. Liu, R. Pan, H. Ding, L. Gu, Y. Yang, C. Li, Y. Xu, R. Hu, H. Chen, X. Zhang, Y. Nie
• Journal: Molecular Oncology
• Published: 2021;15(12):3738-3752
• Cited by: 10 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

ATM serine/threonine kinase (ATM; previously known as ataxia-telangiectasia mutated) plays a critical role in maintaining genomic stability and regulates multiple downstream pathways, such as DNA repair, cell cycle arrest, and apoptosis. As a serine/threonine kinase, ATM has an array of downstream phosphorylation substrates, including checkpoint effector checkpoint kinase 2 (CHK2). ATM inhibits cell cycle progression by phosphorylating and activating CHK2, which plays an important role in the formation and development of tumors and participates in DNA repair responses after double-stranded DNA breaks. In this study, we used a recently developed mammalian functional genetic screening system to explore a series of ATM substrates and their role in DNA damage to enhance our understanding of the DNA damage response. Ubiquilin 4 (UBQLN4), which belongs to the ubiquilin family characterized by its ubiquitin-like (UBL) and ubiquitin-associated (UBA) domains, was identified as a new substrate for ATM. UBQLN4 is involved in various intracellular processes, such as autophagosome maturation, p21 regulation, and motor axon morphogenesis. However, the biological function of UBQLN4 remains to be elucidated. In this study, we not only identified UBQLN4 as a substrate for ATM, but also found that UBQLN4 interacts with and stabilizes the anti-apoptotic proteins Bcl-2-related protein A1 (BCL2A1) and Bcl-2-like protein 10 (BCL2L10) and prevents mesothelioma cell apoptosis in response to DNA damage. These findings expand our understanding of the role of UBQLN4 in mesothelioma and provide new insights into potential mesothelioma treatments targeting substrates for ATM.

© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

In plain English

This was a laboratory study of cells and tumor tissue. It did not study asbestos exposure. The authors used a genetic screen in mouse lymphoma cells to test 52 candidate targets of ATM, an enzyme that responds to DNA damage. They identified UBQLN4 as a new ATM target, modified at a site called Ser318 after DNA damage. In a human mesothelioma cell line (NCI-H2452) treated with the DNA-damaging drug camptothecin, switching off UBQLN4 lowered cell survival and raised apoptosis (programmed cell death), without changing the cell cycle. UBQLN4 bound to two anti-apoptotic proteins, BCL2A1 and BCL2L10, and adding extra UBQLN4 to cells increased their levels. In a purchased tissue array, all three proteins stained more strongly in 30 mesothelioma tissues than in 10 adjacent normal tissues, and UBQLN4 levels correlated positively with the other two. In the public TCGA mesothelioma database, patients with low UBQLN4 survived significantly longer. The authors concluded that UBQLN4 inhibits apoptosis in mesothelioma by stabilizing BCL2A1 and BCL2L10. They added that how it does so needs further research.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: functional genetic screen in cultured cells, cell-line experiments, immunohistochemistry of a commercial tissue microarray, and analysis of the public TCGA database
• Who was studied: Mouse Eμ-Myc p19Arf-/- lymphoma cells; the human mesothelioma cell line NCI-H2452; HEK293T and U2OS cell lines; a purchased tissue microarray of 30 mesothelioma tissues and 10 adjacent normal tissues; TCGA mesothelioma data
• Exposure: No asbestos exposure was studied. The mouse lymphoma screen used DNA-damaging drugs (cisplatin, camptothecin, doxorubicin, methotrexate). The NCI-H2452 mesothelioma-cell experiments used camptothecin. Genes were switched off with shRNA.
• Main results:
  • In the mouse lymphoma cell screen, silencing UBQLN4 increased sensitivity to several DNA-damaging drugs (cisplatin, camptothecin and methotrexate)
  • A mutated form of UBQLN4 (S318A) was no longer phosphorylated after DNA damage; the authors identified Ser318 as a major phosphorylation site
  • In the TCGA mesothelioma database, patients with low UBQLN4 levels survived significantly longer than those with high levels (no figures given in the text)
  • In the tissue array, UBQLN4 staining was stronger in the 30 mesothelioma tissues than in the 10 adjacent tissues
  • NCI-H2452 mesothelioma cells lacking UBQLN4 had more apoptosis after camptothecin treatment than control cells
  • Silencing UBQLN4 did not alter the cell cycle of camptothecin-treated NCI-H2452 cells
  • Of six BCL2 family proteins tested, UBQLN4 interacted only with BCL2A1 and BCL2L10
  • Overexpressing UBQLN4 in 293T cells increased BCL2A1 and BCL2L10 levels
  • BCL2A1 and BCL2L10 stained more strongly in tumors than in adjacent tissues, and their expression correlated positively with UBQLN4 in the tissue samples (n=40)
• The authors' conclusion: The authors concluded that UBQLN4 inhibits apoptosis in mesothelioma through the Ser318 phosphorylation site and by stabilizing BCL2A1 and BCL2L10. They also concluded that UBQLN4 may have therapeutic potential for mesothelioma.
• Limitations the authors state:
  • How UBQLN4 stabilizes BCL2A1 and BCL2L10 remains unknown

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Apoptosis.

Related studies

• Licochalcone A induces apoptosis in malignant pleural mesothelioma through downregulation of Sp1 and subsequent activation of mitochondria-related apoptotic pathway — K.H. Kim, G. Yoon, et al. (2015)
• Inhibition of REV3 expression induces persistent DNA damage and growth arrest in cancer cells — P.A. Knobel, I.N. Kotov, et al. (2011)
• Combination of a p53-activating CP-31398 and an MDM2 or a FAK inhibitor produces growth suppressive effects in mesothelioma with wild-type p53 genotype — B. Zhong, M. Shingyoji, et al. (2020)
• A protein kinase Cdelta-dependent protein kinase D pathway modulates ERK1/2 and JNK1/2 phosphorylation and Bim-associated apoptosis by asbestos — S.A. Buder-Hoffmann, A. Shukla, et al. (2009)
• Differential diagnosis of reactive mesothelial cells and malignant mesothelioma cells using the cell proliferation markers minichromosome maintenance protein 7, geminin, topoisomerase II alpha and Ki-67 — F. Kimura, I. Okayasu, et al. (2013)
• Significance of cell proliferation markers (Minichromosome maintenance protein 7, topoisomerase IIalpha and Ki-67) in cavital fluid cytology: can we differentiate reactive mesothelial cells from malignant cells? — F. Kimura, J. Kawamura, et al. (2010)

Browse more research in Molecular Oncology, or return to medical research.