ERβ-driven NOTCH1 expression promotes squamous differentiation and suppresses SCC.

  • Major finding: ERβ-driven NOTCH1 expression promotes squamous differentiation and suppresses SCC.

  • Concept: EGR3, DLX5, and ERβ modulate NOTCH1 expression and are downregulated in SCCs of different tissues.

  • Impact: ERβ agonists may be useful for squamous cell carcinoma differentiation therapy.

NOTCH1 directs cell differentiation in several cell types and acts as a tumor suppressor in squamous cell carcinomas (SCC). NOTCH1 receptor activation is well studied, but transcriptional control of NOTCH1 expression is poorly understood. Brooks and colleagues used an in silico approach to identify putative NOTCH1 transcriptional regulators and knocked down candidates in primary human keratinocytes. Of genes with replicable effects on NOTCH1 gene expression, distalless homeobox 5 (DLX5), early growth response 3 (EGR3), and estrogen receptor β (ERβ; encoded by ESR2) were identified as positive regulators. Both DLX5 and EGR3 regulated NOTCH1 expression by recruiting RNA polymerase II (PolII) to NOTCH1 enhancer and promoter regions, whereas ERβ promoted PolII transcriptional progression. Accordingly, loss of DLX5, EGR3, or ERβ in keratinocytes resulted in reduced NOTCH1 expression and impaired differentiation in organotypic skin culture. Moreover, expression of all three proteins was downregulated in human skin, head and neck, and lung SCC samples, underscoring their importance in NOTCH1-mediated tumor suppression. Analysis of head and neck SCCs also showed significant gender-related differences in gene expression patterns, with squamous differentiation genes more highly expressed in female patients. Skin, lung, and oral SCC cell lines overexpressing ERβ exhibited upregulated NOTCH1 expression and impaired growth in vitro, and SCC cells with increased ERβ expression showed increased tumor differentiation when implanted into immunocompromised mice. Further, treatment with synthetic ERβ agonists enhanced differentiation and increased NOTCH1 expression in human keratinocytes in vitro and significantly retarded growth of human head and neck SCC xenografts in mice. These data bring to light a regulatory network involving ERβ-mediated regulation of NOTCH1 expression that could possibly be exploited for SCC differentiation therapy.

Brooks YS, Ostano P, Jo SH, Dai J, Getsios S, Dziunycz P, et al. Multifactorial ERβ and NOTCH1 control of squamous differentiation and cancer. J Clin Invest 2014 Apr 17 [Epub ahead of print].

©2014 American Association for Cancer Research.
2014