Dual role of CASP8AP2/FLASH in regulating epithelial-to-mesenchymal transition plasticity (EMP).
Dual role of CASP8AP2/FLASH in regulating epithelial-to-mesenchymal transition plasticity (EMP).
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DOI：
10.1016/j.tranon.2023.101837
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发表时间：
2024-01
影响因子：
5
通讯作者：
Dragoi, Ana -Maria
中科院分区：
文献类型：
--
作者：
Catalanotto, Madison;Vaz, Joel Markus;Abshire, Camille;Youngblood, Reneau;Chu, Min;Levine, Herbert;Jolly, Mohit Kumar;Dragoi, Ana -Maria
关键词：
上皮-间充质转化（EMT）是一个发育过程，包括上皮特征的丧失和间充质特征的获得。EMT可塑性（EMP）是癌细胞同时显示上皮和间充质表型的多种杂交状态之间的动态转变，赋予癌细胞在不断变化的环境中的生存优势。在这里，我们将FLASH描述为EMP和多个EMT-TF的调节器。FLASH的缺失导致具有高上皮评分的混合E/M表型。FLASH调节多细胞连接蛋白的表达，在癌症进展中具有确定的作用。FLASH在各种癌细胞系中的表达与上皮评分呈负相关，这与其作为上皮表型阻遏物的功能一致。上皮-间充质转化（EMT）是一个发育过程，包括上皮特征的丧失和间充质特征的获得。癌症中EMT的激活促进了侵袭性特征和癌症侵袭的获得。EMT可塑性（EMP）是癌细胞同时显示上皮和间充质标志物的多种杂交状态之间的动态转变，赋予癌细胞在转移期间不断变化的环境中的存活优势。进行RNAseq分析以评估组蛋白调节剂FLASH、NPAT和SLBP耗尽的癌细胞中的全基因组转录变化。采用定量PCR和Western blot检测mRNA和蛋白水平。对不同的基因组进行计算分析，以确定癌细胞中的上皮和间充质评分，并将FLASH表达与CCLE集合中的EMT标志物相关联。我们证明，即使在TGFβ存在下，癌细胞中FLASH的丢失也会产生具有高上皮评分的混合E/M表型，如通过使用预定的上皮和间充质基因组表达的计算方法所确定的。参与细胞-细胞连接形成的多个基因在FLASH缺失的细胞中同样特异性上调，表明FLASH作为上皮表型的阻遏物。此外，癌细胞系中的FLASH表达与上皮评分呈负相关。尽管如此，在FLASH、NPAT或SLBP缺失的细胞中，间充质标志物的亚群明显上调。在FLASH缺失的癌细胞中描述的ZEB 1低/SNAIL高/E-cadherin高表型驱动上皮和间充质标志物共存的混合E/M表型。
Epithelial-to-mesenchymal transition (EMT) is a developmental program that consists of the loss of epithelial features concomitant with the acquisition of mesenchymal features. EMT plasticity (EMP), the dynamic transition between multiple hybrid states in which cancer cells display both epithelial and mesenchymal phenotypes, confers survival advantages for cancer cells in the constantly changing environment. Here we characterize FLASH as a regulator of EMP and multiple EMT-TFs. Loss of FLASH gives rise to a hybrid E/M phenotype with high epithelial scores. FLASH regulates the expression of multiple cell junction proteins with an established role in cancer progression. FLASH expression in various cancer lines is inversely correlated with the epithelial score, consistent with its function as a repressor of the epithelial phenotype. Epithelial-to-mesenchymal transition (EMT) is a developmental program that consists of the loss of epithelial features concomitant with the acquisition of mesenchymal features. Activation of EMT in cancer facilitates the acquisition of aggressive traits and cancer invasion. EMT plasticity (EMP), the dynamic transition between multiple hybrid states in which cancer cells display both epithelial and mesenchymal markers, confers survival advantages for cancer cells in constantly changing environments during metastasis. RNAseq analysis was performed to assess genome-wide transcriptional changes in cancer cells depleted for histone regulators FLASH, NPAT, and SLBP. Quantitative PCR and Western blot were used for the detection of mRNA and protein levels. Computational analysis was performed on distinct sets of genes to determine the epithelial and mesenchymal score in cancer cells and to correlate FLASH expression with EMT markers in the CCLE collection. We demonstrate that loss of FLASH in cancer cells gives rise to a hybrid E/M phenotype with high epithelial scores even in the presence of TGFβ, as determined by computational methods using expression of predetermined sets of epithelial and mesenchymal genes. Multiple genes involved in cell-cell junction formation are similarly specifically upregulated in FLASH-depleted cells, suggesting that FLASH acts as a repressor of the epithelial phenotype. Further, FLASH expression in cancer lines is inversely correlated with the epithelial score. Nonetheless, subsets of mesenchymal markers were distinctly up-regulated in FLASH, NPAT, or SLBP-depleted cells. The ZEB1low/SNAILhigh/E-cadherinhigh phenotype described in FLASH-depleted cancer cells is driving a hybrid E/M phenotype in which epithelial and mesenchymal markers coexist.
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影响因子：
5.5
作者：
Mandal S;Tejaswi T;Janivara R;Srikrishnan S;Thakur P;Sahoo S;Chakraborty P;Sohal SS;Levine H;George JT;Jolly MK
通讯作者：
Jolly MK
EMT亚型影响上皮可塑性和细胞迁移模式。
影响因子：
11.8
作者：
Aiello NM;Maddipati R;Norgard RJ;Balli D;Li J;Yuan S;Yamazoe T;Black T;Sahmoud A;Furth EE;Bar-Sagi D;Stanger BZ
通讯作者：
Stanger BZ
影响因子：
7.3
作者：
Gonzalez DM;Medici D
通讯作者：
Medici D
影响因子：
37.3
作者：
Alm-Kristiansen AH;Lorenzo PI;Molværsmyr AK;Matre V;Ledsaak M;Sæther T;Gabrielsen OS
通讯作者：
Gabrielsen OS
影响因子：
11.2
作者：
Dragoi AM;Swiss R;Gao B;Agaisse H
通讯作者：
Agaisse H