Ets family proteins regulate the EMT transcription factors Snail and ZEB in cancer cells

• Published in: FEBS open bio 2022-07, Vol.12 (7), p.1353-1364
• Main Authors: Ichikawa, Mai Koizumi, Endo, Kaori, Itoh, Yuka, Osada, Asami Hotta, Kimura, Yujiro, Ueki, Koichiro, Yoshizawa, Kunio, Miyazawa, Keiji, Saitoh, Masao
• Format: Article
• Language: English
• Subjects: Alternative splicing; Breast cancer; Cancer; Cell culture; Cooperation; EMT; ETS protein; Ets-1 protein; Ets-2 protein; Ets1; Growth factors; Mesenchyme; Motility; Mutation; Phenotypes; Phosphorylation; Proteins; Senescence; siRNA; snail; Snail protein; TGF‐β; Transcription factors; Transforming growth factor-b; Tumors; ZEB1
• ISSN: 2211-5463; 2211-5463
• DOI: 10.1002/2211-5463.13415

The epithelial–mesenchymal transition (EMT) is a crucial morphological event that occurs during epithelial tumor progression. Snail and ZEB1/2 (ZEB1 and ZEB2), known as EMT transcription factors, are key regulators of this transition. ZEB1/2 are positively correlated with EMT phenotypes and the aggressiveness of cancers. On the contrary, Snail is also correlated with the aggressiveness of cancers, but is not correlated with the expression of EMT marker proteins. Snail is induced by transforming growth factor‐β (TGF‐β), a well‐known inducer of EMT, in various cancer cells. Interestingly, Snail induction by TGF‐β is markedly enhanced by active Ras signals. Thus, cancer cells harboring an active Ras mutation exhibit a drastic induction of Snail by TGF‐β alone. Here, we found that members of the E26 transformation‐specific (Ets) transcription factor family, Ets1 and Ets2, contribute to the upregulation of both Snail and ZEB1/2. Snail induction by TGF‐β and active Ras is dramatically inhibited using siRNAs against both Ets1 and Ets2 together, but not on their own; in addition, siRNAs against both Ets1 and Ets2 also downregulate the constitutive expression of Snail and ZEB1/2 in cancer cells. Examination of several alternatively spliced variants of Ets1 revealed that p54‐Ets1, which includes exon VII, but not p42‐Ets1, which excludes exon VII, regulates the expression of the EMT transcription factors, suggesting that Ets1 is a crucial molecule for regulating Snail and ZEB1/2, and thus cancer progression is mediated through post‐translational modification of the exon VII domain. Among key EMT transcription factors, ZEB1/2 are positively correlated with the mesenchymal marker proteins, whereas Snail is not correlated with EMT marker proteins, but largely regulates cellular senescence. Importantly, members of the Ets transcription factor family, Ets1 and Ets2, contribute to the upregulation of both Snail and ZEB1/2 in cancer cells.