The Identification of Potential Therapeutic Targets for Cutaneous Squamous Cell Carcinoma

  • J Invest Dermatol. 2020 Jun;140(6):1154-1165.e5. doi: 10.1016/j.jid.2019.09.024.
Angela McHugh  1 ,  Kenneth Fernandes  1 ,  Nerime Chinner  1 ,  Adel F M Ibrahim  2 ,  Amit K Garg  2 ,  Garry Boag  1 ,  Lydia A Hepburn  1 ,  Charlotte M Proby  3 ,  Irene M Leigh  4 ,  Mark K Saville  5
Affiliations
  • 1. Division of Cancer Research, School of Medicine, University of Dundee, Dundee, United Kingdom.
  • 2. MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, United Kingdom.
  • 3. Division of Cancer Research, School of Medicine, University of Dundee, Dundee, United Kingdom; Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, United Kingdom.
  • 4. Division of Cancer Research, School of Medicine, University of Dundee, Dundee, United Kingdom; Institute of Dentistry, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
  • 5. Division of Cancer Research, School of Medicine, University of Dundee, Dundee, United Kingdom. Electronic address: [email protected].
PMID: 31705877 DOI: 10.1016/j.jid.2019.09.024
Abstract

We performed a small interfering RNA screen to identify targets for cutaneous squamous cell carcinoma (cSCC) therapy in the ubiquitin/ubiquitin-like 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 the 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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