Data from MAB21L4 Deficiency Drives Squamous Cell Carcinoma via Activation of RET

• DOI: 10.1158/0008-5472.c.6514149.v1
• Publication Date: 2023-03-31T21:15:45Z
• Authors: Ankit Srivastava; Cristina Tommasi; Dane Sessions; Angela Mah; Tomas Bencomo; Jasmine M. Garcia; Tiffany Jiang; Michael Lee; Joseph Y. Shen; Lek Wei Seow; Audrey Nguyen; Kimal Rajapakshe; Cristian Coarfa; Kenneth Y. Tsai; Vanessa Lopez-Paj...; Carolyn S. Lee

<div>Abstract<p>Epithelial squamous cell carcinomas (SCC) most commonly originate in the skin, where they display disruptions normally tightly regulated homeostatic balance between keratinocyte proliferation and terminal differentiation. We performed a transcriptome-wide screen for genes of unknown function that possess inverse expression patterns differentiating keratinocytes compared with cutaneous SCC (cSCC), leading to identification <i>MAB21L4</i> (<i>C2ORF54</i>) as an enforcer differentiation suppresses carcinogenesis. Loss MAB21L4 human cSCC organoids increased RET enable malignant progression. In addition transcriptional upregulation RET, deletion preempted recruitment CacyBP-Siah1 E3 ligase complex reduced its ubiquitylation. <i>in vivo</i> tumor models, genetic disruption <i>RET</i> or selective inhibition BLU-667 (pralsetinib) suppressed growth while inducing concomitant Overall, loss early during development blocks by increasing expression. These results suggest targeting activation is potential therapeutic strategy treating SCC.</p>Significance:<p>Downregulation mediated MAB21L4–CacyBP interaction required induce epidermal suppress carcinogenesis, suggesting approach carcinoma.</p></div>