The Identification of Potential Therapeutic Targets for Cutaneous Squamous Cell Carcinoma

Angela McHugh, Kenneth Fernandes, Nerime Chinner, Adel F M Ibrahim, Amit K Garg, Garry Boag, Lydia A Hepburn, Charlotte M Proby, Irene M Leigh, Mark K Saville (Lead / Corresponding author)

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Abstract

We carried out an siRNA screen to identify targets for cutaneous squamous cell carcinoma (cSCC) therapy in the ubiquitin/ubiquitin-like (UBL) system. We provide evidence for selective anti-cSCC activity of knockdown of the E3 ubiquitin ligase MARCH4, the ATPase p97/VCP, the deubiquitinating enzyme USP8, the cullin-RING ligase (CRL) 4 substrate receptor CDT2/DTL and components of the anaphase promoting complex/cyclosome (APC/C). Specifically attenuating CRL4CDT2 by CDT2 knockdown can be more potent in killing cSCC cells than targeting CRLs or CRL4s in general by RBX1 or DDB1 depletion. Suppression of APC/C or forced APC/C activation by targeting its repressor EMI1 are both potential therapeutic approaches. We observed that cSCC cells can be selectively killed by small-molecule inhibitors of USP8 (DUBs-IN-3/compound 22c) and the NEDD8 E1 activating enzyme/CRLs (MLN4924/pevonedistat). A substantial proportion of cSCC cell lines are very highly MLN4924-sensitive. Pathways that respond to defects in proteostasis are involved in the anti-cSCC activity of p97 suppression. Targeting USP8 can reduce the expression of growth factor receptors that participate in cSCC development. EMI1 and CDT2 depletion can selectively cause DNA re-replication and DNA damage in cSCC cells.

Original languageEnglish
Number of pages37
JournalJournal of Investigative Dermatology
Early online date6 Nov 2019
DOIs
Publication statusE-pub ahead of print - 6 Nov 2019

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Squamous Cell Carcinoma
Skin
Anaphase-Promoting Complex-Cyclosome
Therapeutics
Ubiquitin
Cullin Proteins
Ubiquitin-Protein Ligases
Growth Factor Receptors
Epithelial Cells
DNA
Enzymes
Ligases
Cell- and Tissue-Based Therapy
DNA Replication
Small Interfering RNA
DNA Damage
Chemical activation
Cells
Cell Line
Defects

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title = "The Identification of Potential Therapeutic Targets for Cutaneous Squamous Cell Carcinoma",
abstract = "We carried out an siRNA screen to identify targets for cutaneous squamous cell carcinoma (cSCC) therapy in the ubiquitin/ubiquitin-like (UBL) system. We provide evidence for selective anti-cSCC activity of knockdown of the E3 ubiquitin ligase MARCH4, the ATPase p97/VCP, the deubiquitinating enzyme USP8, the cullin-RING ligase (CRL) 4 substrate receptor CDT2/DTL and components of the anaphase promoting complex/cyclosome (APC/C). Specifically attenuating CRL4CDT2 by CDT2 knockdown can be more potent in killing cSCC cells than targeting CRLs or CRL4s in general by RBX1 or DDB1 depletion. Suppression of APC/C or forced APC/C activation by targeting its repressor EMI1 are both potential therapeutic approaches. We observed that cSCC cells can be selectively killed by small-molecule inhibitors of USP8 (DUBs-IN-3/compound 22c) and the NEDD8 E1 activating enzyme/CRLs (MLN4924/pevonedistat). A substantial proportion of cSCC cell lines are very highly MLN4924-sensitive. Pathways that respond to defects in proteostasis are involved in the anti-cSCC activity of p97 suppression. Targeting USP8 can reduce the expression of growth factor receptors that participate in cSCC development. EMI1 and CDT2 depletion can selectively cause DNA re-replication and DNA damage in cSCC cells.",
author = "Angela McHugh and Kenneth Fernandes and Nerime Chinner and Ibrahim, {Adel F M} and Garg, {Amit K} and Garry Boag and Hepburn, {Lydia A} and Proby, {Charlotte M} and Leigh, {Irene M} and Saville, {Mark K}",
note = "This study was supported by DEBRA International and funded by DEBRA Austria (Saville-Proby 1). I.M.L/M.K.S were supported by an ERC Advanced Investigator Award (250170). C.M.P./I.M.L. were supported by a Cancer Research-UK Programme Grant (A13044). Copyright {\circledC} 2019 The Authors. Published by Elsevier Inc. All rights reserved.",
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language = "English",
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The Identification of Potential Therapeutic Targets for Cutaneous Squamous Cell Carcinoma. / McHugh, Angela; Fernandes, Kenneth; Chinner, Nerime; Ibrahim, Adel F M; Garg, Amit K; Boag, Garry; Hepburn, Lydia A; Proby, Charlotte M; Leigh, Irene M; Saville, Mark K (Lead / Corresponding author).

In: Journal of Investigative Dermatology, 06.11.2019.

Research output: Contribution to journalArticle

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AU - Chinner, Nerime

AU - Ibrahim, Adel F M

AU - Garg, Amit K

AU - Boag, Garry

AU - Hepburn, Lydia A

AU - Proby, Charlotte M

AU - Leigh, Irene M

AU - Saville, Mark K

N1 - This study was supported by DEBRA International and funded by DEBRA Austria (Saville-Proby 1). I.M.L/M.K.S were supported by an ERC Advanced Investigator Award (250170). C.M.P./I.M.L. were supported by a Cancer Research-UK Programme Grant (A13044). Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

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N2 - We carried out an siRNA screen to identify targets for cutaneous squamous cell carcinoma (cSCC) therapy in the ubiquitin/ubiquitin-like (UBL) system. We provide evidence for selective anti-cSCC activity of knockdown of the E3 ubiquitin ligase MARCH4, the ATPase p97/VCP, the deubiquitinating enzyme USP8, the cullin-RING ligase (CRL) 4 substrate receptor CDT2/DTL and components of the anaphase promoting complex/cyclosome (APC/C). Specifically attenuating CRL4CDT2 by CDT2 knockdown can be more potent in killing cSCC cells than targeting CRLs or CRL4s in general by RBX1 or DDB1 depletion. Suppression of APC/C or forced APC/C activation by targeting its repressor EMI1 are both potential therapeutic approaches. We observed that cSCC cells can be selectively killed by small-molecule inhibitors of USP8 (DUBs-IN-3/compound 22c) and the NEDD8 E1 activating enzyme/CRLs (MLN4924/pevonedistat). A substantial proportion of cSCC cell lines are very highly MLN4924-sensitive. Pathways that respond to defects in proteostasis are involved in the anti-cSCC activity of p97 suppression. Targeting USP8 can reduce the expression of growth factor receptors that participate in cSCC development. EMI1 and CDT2 depletion can selectively cause DNA re-replication and DNA damage in cSCC cells.

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DO - 10.1016/j.jid.2019.09.024

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