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. Epub 2019 Nov 6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Squamous Cell / drug therapy*
  • Carcinoma, Squamous Cell / pathology
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cyclopentanes / pharmacology
  • Cyclopentanes / therapeutic use
  • Drug Screening Assays, Antitumor
  • Endopeptidases / genetics
  • Endopeptidases / metabolism
  • Endosomal Sorting Complexes Required for Transport / antagonists & inhibitors
  • Endosomal Sorting Complexes Required for Transport / genetics
  • Endosomal Sorting Complexes Required for Transport / metabolism
  • F-Box Proteins / antagonists & inhibitors
  • F-Box Proteins / genetics
  • F-Box Proteins / metabolism
  • Gene Knockdown Techniques
  • Humans
  • Molecular Targeted Therapy / methods
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use
  • RNA, Small Interfering / metabolism
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / pathology
  • Ubiquitin Thiolesterase / antagonists & inhibitors
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin Thiolesterase / metabolism
  • Ubiquitin-Activating Enzymes / antagonists & inhibitors
  • Ubiquitin-Activating Enzymes / genetics
  • Ubiquitin-Activating Enzymes / metabolism

Substances

  • Cell Cycle Proteins
  • Cyclopentanes
  • DTL protein, human
  • Endosomal Sorting Complexes Required for Transport
  • F-Box Proteins
  • FBXO5 protein, human
  • Nuclear Proteins
  • Pyrimidines
  • RNA, Small Interfering
  • Endopeptidases
  • USP8 protein, human
  • Ubiquitin Thiolesterase
  • Ubiquitin-Activating Enzymes
  • NAE protein, human
  • pevonedistat