MAB21L4 Deficiency Drives Squamous Cell Carcinoma via Activation of RET

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-Pajares
Carolyn S Lee

Publication Date

9-2-2022

Journal

Cancer Research

DOI

10.1158/0008-5472.CAN-22-0047

PMID

35705526

PMCID

PMC9444977

PubMedCentral® Posted Date

3-2-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Humans, Calcium-Binding Proteins, Carcinogenesis, Carcinoma, Squamous Cell, Cell Proliferation, Keratinocytes, Proto-Oncogene Proteins c-ret, Skin Neoplasms, squamous cell carcinoma, RET, MAB21L4, C2orf54, CacyBP

Abstract

UNLABELLED: Epithelial squamous cell carcinomas (SCC) most commonly originate in the skin, where they display disruptions in the 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 in differentiating keratinocytes compared with cutaneous SCC (cSCC), leading to the identification of MAB21L4 (C2ORF54) as an enforcer of terminal differentiation that suppresses carcinogenesis. Loss of MAB21L4 in human cSCC organoids increased expression of RET to enable malignant progression. In addition to transcriptional upregulation of RET, deletion of MAB21L4 preempted recruitment of the CacyBP-Siah1 E3 ligase complex to RET and reduced its ubiquitylation. In SCC organoids and in vivo tumor models, genetic disruption of RET or selective inhibition of RET with BLU-667 (pralsetinib) suppressed SCC growth while inducing concomitant differentiation. Overall, loss of MAB21L4 early during SCC development blocks differentiation by increasing RET expression. These results suggest that targeting RET activation is a potential therapeutic strategy for treating SCC.

SIGNIFICANCE: Downregulation of RET mediated by MAB21L4-CacyBP interaction is required to induce epidermal differentiation and suppress carcinogenesis, suggesting RET inhibition as a potential therapeutic approach in squamous cell carcinoma.

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