The Identification of Potential Therapeutic Targets for Cutaneous Squamous Cell Carcinoma

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 CRL4 CDT2 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.

Valosin-Containing Protein (VCP)/p97: A Prognostic Biomarker and Therapeutic Target in Cancer

“…McHugh et al (2020) evaluated the effect of VCP/p97 on the viability of three squamous cell carcinoma (cSCC)cell lines (SCCRDEB4, SCCRDEBMet, and SCCTMet) compared to two normal skin cell lines (NHF and NHK) and reported that VCPsiRNAs killed cSCC cells but not normal skin cells. Cell death caused by VCP depletion was attenuated by the suppression of proteins involved in the response to the accumulation of unfolded proteins in the ER (ATF6, IRE1a/JNK1, and PKR/eiF2α) and amino acid depletion (GCN2/eiF2α) [ 116 ].…”

“…Thus, VCP/p97 represents a potential prognostic biomarker and a therapeutic target. [71] Gastric cancer greater tumor size, presence of vascular and lymphatic invasion, lymph node metastasis, and shorter overall and disease free survival [72] cell survival, degradation of cellular regulators, and gastric carcinogenesis [73,74] low levels of CHOP and DR5 [75] Esophageal cancer higher frequencies of lymph node metastasis, deeper invasion, metastasis, and shorter disease free and overall survival [76] shorter overall survival [77] Breast cancer shorter overall survival [78] poor outcomes of triple-negative patients receiving chemotherapy [79,80] Hematological cancer tumor grade, stage, histological subtype, recurrence and shorter overall and disease-free survival of patients with B-cell lymphoma [104] multiple myeloma development and progression [105] poor prednisone responders in pediatric patients with acute lymphoblastic leukemia [106] exosome generation and secretion in Jurkat tumor cells [107] Melanoma advanced radiotherapy [108] immune escape [109] Glioblastoma radiosensitivity of glioblastoma cells, and survival time of xenografted mice with radiation treatment [110,111] HDAC6 levels and temozolomide resistance therapy [112] Ovarian cancer chemotherapy response in patients receiving the platinum-taxane combination [113] Testicular cancer development of different types of human testicular tumors [114] Bladder cancer shorter survival following bladder removal by cystectomy [115] Squamous cell carcinoma development of squamous cell carcinoma [116] 3.1. VCP/p97 in Gastrointestinal Cancers 3.1.1.…”

<p>Down-Regulation of USP8 Suppresses HER-3 Positive Gastric Cancer Cells Proliferation</p>

“…6,7 Ubiquitination is one of the most important histone modifications and has been reported to be involved in the progress of GC frequently. 8,9 As a member of the deubiquitinating enzymes (DUBs) family, USP8 has been proved to be closely related to the occurrence and development of tumors, 10,11 including breast cancer, 12,13 lung cancer, 14 bladder cancer, 15 cervical cancer, 16 etc. USP8 was originally identified as a growth regulated ubiquitinspecific protease and is like many other DUBs characterized by its multidomain architecture.…”

The Impact of the Ubiquitin System in the Pathogenesis of Squamous Cell Carcinomas

“…The genomic profile of human SCCs has revealed that many CRL-related genes are subjected to cancer-associated genetic alterations, which include gene amplification, deletion and mutation [47]. Remarkably, the anti-tumorigenic action of the neddylation pathway inhibitor MLN4924 in various SCC subtypes clearly illustrates the critical role of CRLs activity in promoting and sustaining SCC pathogenesis [85][86][87]. In line with this, the expression signature of a subset of CRL-related genes defines HNSCC with unfavorable prognosis.…”