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Loss of DLX3 tumor suppressive function promotes progression of SCC through EGFR–ERBB2 pathway

Oncogene volume 40, pages 3680–3694 (2021)Cite this article

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Abstract

Cutaneous squamous cell carcinoma (cSCC) ranks second in the frequency of all skin cancers. The balance between keratinocyte proliferation and differentiation is disrupted in the pathological development of cSCC. DLX3 is a homeobox transcription factor which plays pivotal roles in embryonic development and epidermal homeostasis. To investigate the impact of DLX3 expression on cSCC prognosis, we carried out clinicopathologic analysis of DLX3 expression which showed statistical correlation between tumors of higher pathologic grade and levels of DLX3 protein expression. Further, Kaplan–Meier survival curve analysis demonstrated that low DLX3 expression correlated with poor patient survival. To model the function of Dlx3 in skin tumorigenesis, a two-stage dimethylbenzanthracene (DMBA)/12-O-tetradecanoylphorbol 13-acetate (TPA) study was performed on mice genetically depleted of Dlx3 in skin epithelium (Dlx3cKO). Dlx3cKO mice developed significantly more tumors, with more rapid tumorigenesis compared to control mice. In Dlx3cKO mice treated only with DMBA, tumors developed after ~16 weeks suggesting that loss of Dlx3 has a tumor promoting effect. Whole transcriptome analysis of tumor and skin tissue from our mouse model revealed spontaneous activation of the EGFR–ERBB2 pathway in the absence of Dlx3. Together, our findings from human and mouse model system support a tumor suppressive function for DLX3 in skin and underscore the efficacy of therapeutic approaches that target EGFR–ERBB2 pathway.

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Fig. 1: Decreased expression of DLX3 correlates with skin cancer progression and poor survival in patients.
Fig. 2: Dlx3 deficiency enhances the development of DMBA/TPA-induced skin tumors.
Fig. 3: Dlx3 deficiency drives tumor promotion in single dose DMBA-only model.
Fig. 4: Epidermal-specific deletion of Dlx3 accelerates tumor formation and tumor numbers in triple dose DMBA only model.
Fig. 5: Dlx3 deficiency facilitates conversion of low risk papillomas to high risk papillomas.
Fig. 6: Gene expression profiling of mouse skin and tumor samples from DMBA-only skin carcinogenesis.
Fig. 7: DLX3 downregulates the activation of EGFR and ERBB2 by moderating the expression of EGFR ligands in healthy epidermis.

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Acknowledgements

This work was supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH (ZIA-AR041124 to MIM). We thank Gutierrez-Cruz and S. Dell’Orso of the NIAMS Genome Analysis Core Facility and members of the NIAMS Light Imaging Core Facility. This work used the computational resources of the NIH High-Performance Computing Biowulf Cluster. We also thank all members of our laboratories for their continuous support. BioRender was used to create experimental design schematic.

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Authors and Affiliations

  1. Laboratory of Skin Biology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD, USA

    Deepti Bajpai, Spencer Mehdizadeh, Andrew Sawaya, Andrew Overmiller, Kowser Hasneen, Meghan Kellett, Elisabetta Palazzo & Maria I. Morasso

  2. Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Japan

    Akihiko Uchiyama, Yuta Inoue & Sei-ichiro Motegi

  3. Biodata Mining and Discovery Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD, USA

    Stephen R. Brooks

  4. Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA

    Stuart H. Yuspa & Christophe Cataisson

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Contributions

DB, SM, CC, AU, and MIM conceptualize the work; DB, SM, CC, AU, and MIM designed research; DB, SM, CC, AU, YI, MK, EP, and KH performed research; DB, SM, CC, AU, YI, AS, AO, SRB, MK, EP, SM, SY, and MIM analyzed data; and DB, SM, and MIM wrote the paper.

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Correspondence to Maria I. Morasso.

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Bajpai, D., Mehdizadeh, S., Uchiyama, A. et al. Loss of DLX3 tumor suppressive function promotes progression of SCC through EGFR–ERBB2 pathway. Oncogene 40, 3680–3694 (2021). https://doi.org/10.1038/s41388-021-01802-9

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