The Identification of Potential Therapeutic Targets for Cutaneous Squamous Cell Carcinoma

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Cutaneous squamous cell carcinoma (cSCC) is a common skin cancer with limited targeted therapies.
• The ubiquitin/ubiquitin-like system plays crucial roles in cellular processes, making it a potential source for therapeutic targets.

Purpose of the Study:

• To identify novel therapeutic targets for cutaneous squamous cell carcinoma (cSCC) within the ubiquitin/ubiquitin-like system.
• To evaluate the selective anti-cSCC activity of targeting specific components of this system.

Main Methods:

• A small interfering RNA (siRNA) screen was employed to identify potential therapeutic targets.
• Selective small-molecule inhibitors were used to validate the efficacy of targeting specific proteins.
• siRNA-mediated depletion was used to investigate the role of CDT2 and EMI1.

Main Results:

• Knockdown of E3 ubiquitin ligase MARCH4, ATPase p97/VCP, deubiquitinating enzyme USP8, CRL4 substrate receptor CDT2/DTL, and APC/C components demonstrated selective anti-cSCC activity.
• CDT2 depletion was more potent in killing cSCC cells than general CRL targeting.
• Small-molecule inhibitors of USP8 and MLN4924 (NEDD8 E1 activating enzyme/CRLs) selectively killed cSCC cells, with many cell lines showing high sensitivity to MLN4924.
• p97 suppression activated proteostasis pathways, USP8 targeting reduced growth factor receptor expression, and EMI1/CDT2 depletion induced DNA re-replication and damage in cSCC cells.

Conclusions:

• The ubiquitin/ubiquitin-like system offers promising therapeutic targets for cSCC.
• Targeting specific components like MARCH4, p97/VCP, USP8, CDT2, and APC/C, or utilizing inhibitors like MLN4924, presents viable strategies for cSCC treatment.
• Further investigation into these targets could lead to novel therapeutic approaches for cSCC.