The polarity protein Scrib mediates epidermal development and exerts a tumor suppressive function during skin carcinogenesis

Abstract

BackgroundThe establishment and maintenance of polarity is vital for embryonic development and loss of polarity is a frequent characteristic of epithelial cancers, however the underlying molecular mechanisms remain unclear. Here, we identify a novel role for the polarity protein Scrib as a mediator of epidermal permeability barrier acquisition, skeletal morphogenesis, and as a potent tumor suppressor in cutaneous carcinogenesis.MethodsTo explore the role of Scrib during epidermal development, we compared the permeability of toluidine blue dye in wild-type, Scrib heterozygous and Scrib KO embryonic epidermis at E16.5, E17.5 and E18.5. Mouse embryos were stained with alcian blue and alizarin red for skeletal analysis. To establish whether Scrib plays a tumor suppressive role during skin tumorigenesis and/or progression, we evaluated an autochthonous mouse model of skin carcinogenesis in the context of Scrib loss. We utilised Cre-LoxP technology to conditionally deplete Scrib in adult epidermis, since Scrib KO embryos are neonatal lethal.ResultsWe establish that Scrib perturbs keratinocyte maturation during embryonic development, causing impaired epidermal barrier formation, and that Scrib is required for skeletal morphogenesis in mice. Analysis of conditional transgenic mice deficient for Scrib specifically within the epidermis revealed no skin pathologies, indicating that Scrib is dispensable for normal adult epidermal homeostasis. Nevertheless, bi-allelic loss of Scrib significantly enhanced tumor multiplicity and progression in an autochthonous model of epidermal carcinogenesis in vivo, demonstrating Scrib is an epidermal tumor suppressor. Mechanistically, we show that apoptosis is the critical effector of Scrib tumor suppressor activity during skin carcinogenesis and provide new insight into the function of polarity proteins during DNA damage repair.ConclusionsFor the first time, we provide genetic evidence of a unique link between skin carcinogenesis and loss of the epithelial polarity regulator Scrib, emphasizing that Scrib exerts a wide-spread tumor suppressive function in epithelia.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0440-z) contains supplementary material, which is available to authorized users.

Tumor-suppressive functions of long-chain acyl-CoA synthetase 4 in gastric cancer

“…These observations provide new insights into ACSL4 function on cell proliferation and migration in a tissue‐specific or –dependent manner. In addition, it is reported previously that one gene can exert distinct even contrary functions in different tissues, such as Klf4 and Scribble , supporting the feature of ACSL4 with opposite effects in different cancers.…”

Iron modulation of erythropoiesis is associated with Scribble-mediated control of the erythropoietin receptor

“…Our studies therefore focused on animals with germline excision (Δ). Because of the neonatal (P0) lethality of Scrib Δ/Δ mice ( Pearson et al, 2015 ), we analyzed fetal livers at day 13.5 after conception. In these specimens, deletion of Scrib was associated with significantly reduced liver cellularity ( Fig.…”

Structural analysis of phosphorylation‐associated interactions of human MCC with Scribble PDZ domains

“…This article is protected by copyright. All rights reserved suppress tumors was shown to be conserved across species, with Scribble knock-out promoting tumor initiation, and when coupled with oncogenic drivers including RAS, tumor progression in diverse epithelial tissues including mammary, prostate, skin and the lung [6][7][8][9][10].…”