Reversal of CYLD phosphorylation as a novel therapeutic approach for adult T-cell leukemia/lymphoma (ATLL)

Xu, Xin; Kalac, Matko; Markson, Michael; Chan, Mark; Brody, Joshua; Bhagat, Govind; Ang, Rosalind L.; Legarda, Diana; Justus, Scott J.; Liu, Feng; Liu, Qingshan; Xiong, Huabao; Ting, Adrian T.

doi:10.1038/s41419-020-2294-6

Cited by 23 publications

(20 citation statements)

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“…In lymphoma like CLL, CYLD protein expression levels was lower in tumor invasive lymph node than in normal lymph node samples [ 49 ]. But in our previous research about T cell lymphoma,total CYLD protein expression levels was no significant difference between tumor invasive lymph node and normal lymph node samples [ 24 ]. These findings suggest that there are different mechanisms of functional regulation of CYLD in different tumors.…”

Section: Discussionmentioning

confidence: 97%

“…The research on how CYLD phosphorylation regulate the occurrence and development of hematological malignances is still lacking. Our previous study indicated high protein expression levels of CYLD phosphorylation in adult T-cell leukemia/lymphoma (ATLL) and regulating CYLD phosphorylation could regulate CYLD ubiquitin activity to improve ATLL cells apoptosis [ 24 ]. Whether CYLD phosphorylation is also a regulator for non-GCB-DLBCL apoptosis needs further research.…”

Section: Discussionmentioning

confidence: 99%

“…When serine in this region is mutated into alanine, CYLD cannot be phosphorylated, and its activity will be significantly enhanced, which will impact on CYLD ubiquitination function, resulting in the generation of apoptosis signal through NFκB signaling pathway [ 22 , 23 ]. Our previous research has demonstrated that adult T-cell leukemia/lymphoma (ATLL) had high level of CYLD phosphorylation, down-regulating CYLD phosphorylation could increase CYLD deubiquitinase activity and then promoted apoptosis in ATLL [ 24 ]. Whether CYLD phosphorylation is also a therapeutic target for non-GCB-DLBCL is unknown.…”

Section: Introductionmentioning

confidence: 99%

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Down-regulation of cylindromatosis protein phosphorylation by BTK inhibitor promotes apoptosis of non-GCB-diffuse large B-cell lymphoma

Wei

Zhong

et al. 2021

Cancer Cell Int

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Background Non-germinal center B-cell-like diffuse large B-cell lymphoma (non-GCB-DLBCL) has worse clinical outcome than GCB-DLBCL, and some relapsed/refractory non-GCB-DLBCL (R/R non-GCB-DLBCL) are even resistant to CD20 monoclonal antibody (rituximab). Bruton’s tyrosine kinase inhibitors (BTKis) are new drugs for B-cell lymphoma. BTKis can promote apoptosis of DLBCL by inactivating nuclear transcription factor κB (NFκB) signaling pathway. Cylindromatosis (CYLD) is a tumor suppressor and ubiquitinase. CYLD can inactivate NFκB signaling pathway through ubiquitination and regulate the apoptosis of hematological tumors. The ubiquitination of CYLD can be regulated by phosphorylation, suggesting that the regulation of CYLD phosphorylation can be a potential mechanism to promote the apoptosis of hematological tumors. Therefore, we hypothesized that BTKis could promote the apoptosis of non-GCB-DLBCL by regulating the phosphorylation of CYLD, especially in rituximab resistant cases, and we proved this hypothesis through both in vivo and in vitro experiments. Methods The baseline expression levels of CYLD phosphorylation in non-GCB-DLBCL patients and cell lines were detected by Western Blotting. The non-GCB-DLBCL cell lines were treated with BTKis, and apoptosis induced by BTKis treatment was detected by Western blotting, cell viability assay and Annexin V assay. To verify whether the effect of BTKis on apoptosis in non-GCN-DLBCL cells is CYLD dependent, the expression of CYLD was knocked down by lentiviral shRNAs. To verify the effect of BTKis on the phosphorylation of CYLD and the apoptosis in vivo and in rituximab resistant non-GCB-DLBCL, the xeograft model and rituximab resistant non-GCB-DLBCL cells were generated by tumor cell inoculation and escalation of drug concentrations, respectively. Results BTKis induced apoptosis by down-regulating CYLD phosphorylationin in non GCB-DLBCL, xenograft mouse model, and rituximab-resistant cells, and this effect could be enhanced by rituximab. Knocking-down CYLD reversed apoptosis which was induced by BTKis. BTKis induced CYLD-dependent apoptosis in non-GCB-DLBCL including in rituximab-resistant cells. Conclusions The present results indicated that CYLD phosphorylation is a potential clinical therapeutic target for non-GCB-DLBCL, especially for rituximab-resistant relapsed/refractory cases.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Down-regulation of cylindromatosis protein phosphorylation by BTK inhibitor promotes apoptosis of non-GCB-diffuse large B-cell lymphoma

Wei

Zhong

et al. 2021

Cancer Cell Int

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“…Both IKK inhibitors and overexpression of kinase-inactive TBK/IKK can lower CYLD phosphorylation and trigger cell death ( Table 3 ). These results indicated that phosphorylated CYLD is a crucial regulator of ATLL survival and a potential novel therapeutic target for pharmacologic modification in ATLL ( Xu et al, 2020 ).…”

Section: The Therapeutic Potential Of Targeting Ptms In Dubsmentioning

confidence: 88%

Post-Translational Modifications of Deubiquitinating Enzymes: Expanding the Ubiquitin Code

Wang

2021

Front. Pharmacol.

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Post-translational modifications such as ubiquitination play important regulatory roles in several biological processes in eukaryotes. This process could be reversed by deubiquitinating enzymes (DUBs), which remove conjugated ubiquitin molecules from target substrates. Owing to their role as essential enzymes in regulating all ubiquitin-related processes, the abundance, localization, and catalytic activity of DUBs are tightly regulated. Dysregulation of DUBs can cause dramatic physiological consequences and a variety of disorders such as cancer, and neurodegenerative and inflammatory diseases. Multiple factors, such as transcription and translation of associated genes, and the presence of accessory domains, binding proteins, and inhibitors have been implicated in several aspects of DUB regulation. Beyond this level of regulation, emerging studies show that the function of DUBs can be regulated by a variety of post-translational modifications, which significantly affect the abundance, localization, and catalytic activity of DUBs. The most extensively studied post-translational modification of DUBs is phosphorylation. Besides phosphorylation, ubiquitination, SUMOylation, acetylation, oxidation, and hydroxylation are also reported in DUBs. In this review, we summarize the current knowledge on the regulatory effects of post-translational modifications of DUBs.

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“…The loss of CYLD stabilizes the TNFR1 complex and NF-κB activity and consequently suppresses TNFα-induced cell death [128][129][130][131][208][209][210]. In TNFR1 signaling, IKK-mediated phosphorylation at serine 418 of CYLD protects cancer cells against cell death by downregulating CYLD activity [211][212][213]. In addition to NF-κB regulation, CYLD promotes cell death by promoting RIPK1 activity.…”

Section: Cyldmentioning

confidence: 99%

Deubiquitinases: Modulators of Different Types of Regulated Cell Death

Lee

Kim

Hwang

et al. 2021

IJMS

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The mechanisms and physiological implications of regulated cell death (RCD) have been extensively studied. Among the regulatory mechanisms of RCD, ubiquitination and deubiquitination enable post-translational regulation of signaling by modulating substrate degradation and signal transduction. Deubiquitinases (DUBs) are involved in diverse molecular pathways of RCD. Some DUBs modulate multiple modalities of RCD by regulating various substrates and are powerful regulators of cell fate. However, the therapeutic targeting of DUB is limited, as the physiological consequences of modulating DUBs cannot be predicted. In this review, the mechanisms of DUBs that regulate multiple types of RCD are summarized. This comprehensive summary aims to improve our understanding of the complex DUB/RCD regulatory axis comprising various molecular mechanisms for diverse physiological processes. Additionally, this review will enable the understanding of the advantages of therapeutic targeting of DUBs and developing strategies to overcome the side effects associated with the therapeutic applications of DUB modulators.

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Reversal of CYLD phosphorylation as a novel therapeutic approach for adult T-cell leukemia/lymphoma (ATLL)

Cited by 23 publications

References 77 publications

Down-regulation of cylindromatosis protein phosphorylation by BTK inhibitor promotes apoptosis of non-GCB-diffuse large B-cell lymphoma

Down-regulation of cylindromatosis protein phosphorylation by BTK inhibitor promotes apoptosis of non-GCB-diffuse large B-cell lymphoma

Post-Translational Modifications of Deubiquitinating Enzymes: Expanding the Ubiquitin Code

Deubiquitinases: Modulators of Different Types of Regulated Cell Death

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