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Altering MYC phosphorylation in the epidermis increases the stem cell population and contributes to the development, progression, and metastasis of squamous cell carcinoma.
Oncogenesis ( IF 5.9 ) Pub Date : 2020-09-07 , DOI: 10.1038/s41389-020-00261-3
Xiaoyan Wang 1 , Ellen M Langer 1, 2 , Colin J Daniel 1 , Mahnaz Janghorban 1 , Vivian Wu 3 , Xiao-Jing Wang 4, 5 , Rosalie C Sears 1, 2
Affiliation  

cMYC (MYC) is a potent oncoprotein that is subject to post-translational modifications that affect its stability and activity. Here, we show that Serine 62 phosphorylation, which increases MYC stability and oncogenic activity, is elevated while Threonine 58 phosphorylation, which targets MYC for degradation, is decreased in squamous cell carcinoma (SCC). The oncogenic role of MYC in the development of SCC is unclear since studies have shown in normal skin that wild-type MYC overexpression can drive loss of stem cells and epidermal differentiation. To investigate whether and how altered MYC phosphorylation might affect SCC development, progression, and metastasis, we generated mice with inducible expression of MYCWT or MYCT58A in the basal layer of the skin epidermis. In the T58A mutant, MYC is stabilized with constitutive S62 phosphorylation. When challenged with DMBA/TPA-mediated carcinogenesis, MYCT58A mice had accelerated development of papillomas, increased conversion to malignant lesions, and increased metastasis as compared to MYCWT mice. In addition, MYCT58A-driven SCC displayed stem cell gene expression not observed with MYCWT, including increased expression of Lgr6, Sox2, and CD34. In support of MYCT58A enhancing stem cell phenotypes, its expression was associated with an increased number of BrdU long-term label-retaining cells, increased CD34 expression in hair follicles, and increased colony formation from neonatal keratinocytes. Together, these results indicate that altering MYC phosphorylation changes its oncogenic activity—instead of diminishing establishment and/or maintenance of epidermal stem cell populations like wild-type MYC, pS62-MYC enhances these populations and, under carcinogenic conditions, pS62-MYC expression results in aggressive tumor phenotypes.



中文翻译:

改变表皮中的 MYC 磷酸化会增加干细胞数量,并有助于鳞状细胞癌的发展、进展和转移。

cMYC (MYC) 是一种有效的癌蛋白,受翻译后修饰影响其稳定性和活性。在这里,我们发现提高 MYC 稳定性和致癌活性的丝氨酸 62 磷酸化升高,而靶向 MYC 降解的苏氨酸 58 磷酸化在鳞状细胞癌 (SCC) 中降低。MYC 在 SCC 发展中的致癌作用尚不清楚,因为研究表明,在正常皮肤中,野生型 MYC 过表达可导致干细胞损失和表皮分化。为了研究 MYC 磷酸化的改变是否以及如何影响 SCC 的发展、进展和转移,我们生成了具有 MYC WT或 MYC T58A可诱导表达的小鼠在皮肤表皮的基底层。在 T58A 突变体中,MYC 通过组成型 S62 磷酸化稳定。当受到 DMBA/TPA 介导的致癌作用的挑战时,与 MYC WT小鼠相比,MYC T58A小鼠加速了乳头状瘤的发展,增加了向恶性病变的转化,并增加了转移。此外,MYC T58A驱动的 SCC 表现出 MYC WT未观察到的干细胞基因表达,包括Lgr6、Sox2CD34的表达增加。支持MYC T58A增强干细胞表型,其表达与BrdU长期标记保留细胞数量增加、毛囊中CD34表达增加以及新生儿角质形成细胞集落形成增加有关。总之,这些结果表明,改变 MYC 磷酸化会改变其致癌活性——而不是减少表皮干细胞群(如野生型 MYC)的建立和/或维持,pS62-MYC 增强了这些群,并且在致癌条件下,pS62-MYC 表达结果在侵袭性肿瘤表型中。

更新日期:2020-09-08
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