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

Liu, Fang; Pan, Runsang; Ding, H.; Gu, Liling; Yang, Yan; Li, ChuanYin; Xu, Yongjie; Hu, Ronggui; Chen, Hui; Zhang, XiangYan; Nie, Yingjie

doi:10.1002/1878-0261.13058

Cited by 8 publications

(3 citation statements)

References 42 publications

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“…These previous reports support that UBQLN4 is closely related to DNA repair pathways through the interactions with specific response pathways such as key immune factors. The studies also demonstrate the UBQLN4 has multiple functions in responding to DNA damages [ 7 , 8 , 11 , 15 , 42 ] and regulating protein clearance to prevent proteotoxic cell stress an event that would be quite active in proliferating cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Genomic Amplification of UBQLN4 Is a Prognostic and Treatment Resistance Factor

Kobayashi

Bustos

Shoji

et al. 2022

Cells

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Ubiquilin-4 (UBQLN4) is a proteasomal shuttle factor that directly binds to ubiquitylated proteins and delivers its cargo to the 26S proteasome for degradation. We previously showed that upregulated UBQLN4 determines the DNA damage response (DDR) through the degradation of MRE11A. However, the regulatory mechanism at DNA level, transcriptionally and post-transcriptional levels that control UBQLN4 mRNA levels remains unknown. In this study, we screened 32 solid tumor types and validated our findings by immunohistochemistry analysis. UBQLN4 is upregulated at both mRNA and protein levels and the most significant values were observed in liver, breast, ovarian, lung, and esophageal cancers. Patients with high UBQLN4 mRNA levels had significantly poor prognoses in 20 of 32 cancer types. DNA amplification was identified as the main mechanism promoting UBQLN4 upregulation in multiple cancers, even in the early phases of tumor development. Using CRISPR screen datasets, UBQLN4 was identified as a common essential gene for tumor cell viability in 81.1% (860/1,060) of the solid tumor derived cell lines. Ovarian cancer cell lines with high UBQLN4 mRNA levels were platinum-based chemotherapy resistant, while they were more sensitive to poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi). Our findings highlight the utilities of UBQLN4 as a significant pan-cancer theranostic factor and a precision oncology biomarker for DDR-related drug resistance.

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Section: Discussionmentioning

confidence: 99%

Genomic Amplification of UBQLN4 Is a Prognostic and Treatment Resistance Factor

Kobayashi

Bustos

Shoji

et al. 2022

Cells

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“…UBQLN4, a member of the ubiquilin family, shares common characteristics with other UBQLN(Liu et al 2021 ). UBQLN4 is associated with various cellular processes, including apoptosis(Huang et al 2018 ), amyotrophic lateral sclerosis(Thakur et al 2020 ), immune-related therapies(Li et al 2021 ) and DNA damage repair(Jachimowicz et al 2019 ).…”

Section: Discussionmentioning

confidence: 99%

UBQLN4 promotes the proliferation and invasion of non-small cell lung cancer cell by regulating PI3K/AKT pathway

He,

Chen,

Ruan

et al. 2024

J Cancer Res Clin Oncol

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Background Ubiquilin-4 (UBQLN4), a member of the ubiquilin family, has received limited attention in cancer research to date. Here, we investigated for the first time the functional role and mechanism of UBQLN4 in non-small cell lung cancer (NSCLC). Methods The Cancer Genome Atlas (TCGA) database was employed to validate UBQLN4 as a differentially expressed gene. Expression differences of UBQLN4 in NSCLC cells and tissues were assessed using immunohistochemistry (IHC) experiment and western blotting (WB) experiment. Kaplan-Meier analysis was conducted to examine the association between UBQLN4 expression and NSCLC prognosis. Functional analyses of UBQLN4 were performed through cell counting kit-8 (CCK-8), colony formation, and transwell invasion assays. The impact of UBQLN4 on tumor-associated signaling pathways was assessed using the path scan intracellular signaling array. In vivo tumorigenesis experiments were conducted to further investigate the influence of UBQLN4 on tumor formation. Results UBQLN4 exhibited up-regulation in both NSCLC tissues and cells. Additionally, over-expression of UBQLN4 was associated with an unfavorable prognosis in NSCLC patients. Functional loss analyses demonstrated that inhibiting UBQLN4 could suppress the proliferation and invasion of NSCLC cells in both in vitro and in vivo settings. Conversely, functional gain experiments yielded opposite results. Path scan intracellular signaling array results suggested that the role of UBQLN4 is associated with the PI3K/AKT pathway, a correlation substantiated by in vitro and in vivo tumorigenesis experiments. Conclusion We validated that UBQLN4 promotes proliferation and invasion of NSCLC cells by activating the PI3K/AKT pathway, thereby facilitating the progression of NSCLC. These findings underscore the potential of targeting UBQLN4 as a therapeutic strategy for NSCLC.

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“…Ubiquilin-1-dependent monoubiquitinylation of Bcl-B leads to its stabilization and removal from mitochondria to the cytosol [ 58 ]. Furthermore, another member of the ubiquilin family, ubiquilin-4, stabilizes Bcl-B and prevents apoptosis in mesothelioma cells, which have high Bcl-B expression [ 59 ]. Unfortunately, the mechanisms underlying the stabilization and relocation of Bcl-B after interactions with ubiquilins remain uncertain and require further clarification.…”

Section: Discovery Structure and Protein–protein Interactionsmentioning

confidence: 99%

Bcl-B: an “unknown” protein of the Bcl-2 family

Pervushin,

Kopeina,

Zhivotovsky

2023

Biol Direct

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Bcl-B is a poorly understood protein of the Bcl-2 family that is highly expressed in many healthy tissues and tumor types. Bcl-B is considered an antiapoptotic protein, but many reports have revealed its contradictory roles in different cancer types. In this mini-review, we elucidate the functions of Bcl-B in normal conditions and various pathologies, its regulation of programmed cell death, its oncogene/oncosuppressor activity in tumorigenesis, its impact on drug-acquired resistance, and possible approaches to inhibit Bcl-B.

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

Cited by 8 publications

References 42 publications

Genomic Amplification of UBQLN4 Is a Prognostic and Treatment Resistance Factor

Genomic Amplification of UBQLN4 Is a Prognostic and Treatment Resistance Factor

UBQLN4 promotes the proliferation and invasion of non-small cell lung cancer cell by regulating PI3K/AKT pathway

Bcl-B: an “unknown” protein of the Bcl-2 family

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