SUMMARY Epithelial-mesenchymal transition (EMT) enhances invasiveness and confers tumor cells with cancer stem cell (CSC)-like characteristics. We showed that the Snail-G9a-Dnmt1 complex, which is critical for E-cadherin promoter silencing, is also required for the promoter methylation of fructose-1,6-biphosphatase (FBP1) in basal-like breast cancer (BLBC). Loss of FBP1 induces glycolysis and results in increased glucose uptake, macromolecules biosynthesis, formation of tetrameric PKM2, and maintenance of ATP production under hypoxia. Loss of FBP1 also inhibits oxygen consumption and ROS production by suppressing mitochondrial complex I activity; this metabolic reprogramming results in an increased CSC-like property and tumorigenicity by enhancing the interaction of β-catenin with TCF. Our study indicates that the loss of FBP1 is a critical oncogenic event in EMT and BLBC.

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Epithelial-mesenchymal transition (EMT) is a highly conserved process in which polarized, immotile epithelial cells lose adherent and tight junctions, and become migratory mesenchymal cells. As a key transcriptional repressor of E-cadherin expression in EMT, Snail plays an important role in embryonic development and cancer progression. Emerging evidences indicate that Snail confers tumor cells with cancer stem cell-like traits, and promotes drug resistance, tumor recurrence and metastasis. In this review, we summarize recent developments underlying the regulation and functions of Snail in tumor progression, and discuss new approaches against EMT in preventing metastatic cancers.

Summary Twist is a key transcription activator of epithelial-mesenchymal transition (EMT). It remains unclear how Twist induces gene expression. Here we reported a mechanism by which Twist recruits BRD4 to direct WNT5A expression in basal-like breast cancer (BLBC). Twist contains a “histone H4 mimic” GK-X-GK motif that is di-acetylated by Tip60. The di-acetylated Twist binds the second bromodomain of BRD4, whose first bromodomain interacts with acetylated H4, thereby constructs an activated Twist/BRD4/P-TEFb/RNA-PolII complex at the WNT5A promoter and enhancer. Pharmacologic inhibition of the Twist-BRD4 association reduced WNT5A expression and suppressed invasion, cancer stem cell (CSC)-like properties, and tumorigenicity of BLBC cells. Our study indicates that the interaction with BRD4 is critical for the oncogenic function of Twist in BLBC.

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We compute 1/λ corrections to the four-point functions of half-BPS operators in SU (N ) N = 4 super-Yang-Mills theory at large N and large 't Hooft coupling λ = g 2 YM N using two methods. Firstly, we relate integrals of these correlators to derivatives of the mass deformed S 4 free energy, which was computed at leading order in large N and to all orders in 1/λ using supersymmetric localization. Secondly, we use AdS/CFT to relate these 1/λ corrections to higher derivative corrections to supergravity for scattering amplitudes of Kaluza-Klein scalars in IIB string theory on AdS 5 × S 5 , which in the flat space limit are known from worldsheet calculations. These two methods match at the order corresponding to the tree level R 4 interaction in string theory, which provides a precise check of AdS/CFT beyond supergravity, and allow us to derive the holographic correlators to tree level D 4 R 4 order. Combined with constraints from [1], our results can be used to derive CFT data to one-loop D 4 R 4 order. Finally, we use AdS/CFT to fix these correlators in the limit where N is taken to be large while g YM is kept fixed. In this limit, we present a conjecture for the small mass limit of the S 4 partition function that includes all instanton corrections and is written in terms of the same Eisenstein series that appear in the study of string theory scattering amplitudes.

Breast cancers are highly heterogeneous but can be grouped into subtypes based on several criteria, including level of expression of certain markers. Claudin-low breast cancer (CLBC) is associated with early metastasis and resistance to chemotherapy, while gene profiling indicates it is characterized by the expression of markers of epithelial-mesenchymal transition (EMT) -a phenotypic conversion linked with metastasis. Although the epigenetic program controlling the phenotypic and cellular plasticity of EMT remains unclear, one contributor may be methylation of the E-cadherin promoter, resulting in decreased E-cadherin expression, a hallmark of EMT. Indeed, reduced E-cadherin often occurs in CLBC and may contribute to the early metastasis and poor patient survival associated with this disease. Here, we have determined that methylation of histone H3 on lysine 9 (H3K9me2) is critical for promoter DNA methylation of E-cadherin in three TGF-β-induced EMT model cell lines, as well as in CLBC cell lines. Further, Snail interacted with G9a, a major euchromatin methyltransferase responsible for H3K9me2, and recruited G9a and DNA methyltransferases to the E-cadherin promoter for DNA methylation. Knockdown of G9a restored E-cadherin expression by suppressing H3K9me2 and blocking DNA methylation. This resulted in inhibition of cell migration and invasion in vitro and suppression of tumor growth and lung colonization in in vivo models of CLBC metastasis. Our study not only reveals a critical mechanism underlying the epigenetic regulation of EMT but also paves a way for the development of new treatment strategies for CLBC.