Accumulating evidence indicates that the zinc-finger transcription factor ZEB1 is predominantly expressed in the stroma of several tumours. However, the role of stromal ZEB1 in tumour progression remains unexplored. In this study, while interrogating human databases, we uncover a remarkable decrease in relapse-free survival of breast cancer patients expressing high ZEB1 levels in the stroma. Using a mouse model of breast cancer, we show that ZEB1 inactivation in stromal fibroblasts suppresses tumour initiation, progression and metastasis. We associate this with reduced extracellular matrix remodeling, immune cell infiltration and decreased angiogenesis. ZEB1 deletion in stromal fibroblasts increases acetylation, expression and recruitment of p53 to FGF2/7 , VEGF and IL6 promoters, thereby reducing their production and secretion into the surrounding stroma. Importantly, p53 ablation in ZEB1 stroma-deleted mammary tumours sufficiently recovers the impaired cancer growth and progression. Our findings identify the ZEB1/p53 axis as a stroma-specific signaling pathway that promotes mammary epithelial tumours.

The zinc finger transcription factor Snail is aberrantly activated in many human cancers and associated with poor prognosis. Therefore, targeting Snail is expected to exert therapeutic benefit in patients with cancer. However, Snail has traditionally been considered “undruggable,” and no effective pharmacological inhibitors have been identified. Here, we found a small-molecule compound CYD19 that forms a high-affinity interaction with the evolutionarily conserved arginine-174 pocket of Snail protein. In aggressive cancer cells, CYD19 binds to Snail and thus disrupts Snail’s interaction with CREB-binding protein (CBP)/p300, which consequently impairs CBP/p300-mediated Snail acetylation and then promotes its degradation through the ubiquitin-proteasome pathway. Moreover, CYD19 restores Snail-dependent repression of wild-type p53, thus reducing tumor growth and survival in vitro and in vivo. In addition, CYD19 reverses Snail-mediated epithelial-mesenchymal transition (EMT) and impairs EMT-associated tumor invasion and metastasis. Our findings demonstrate that pharmacologically targeting Snail by CYD19 may exert potent therapeutic effects in patients with cancer.

Obesity is a medical condition in which abnormal or excessive fat accumulates to an extent that is associated with various diseases. In our ongoing research to figure out natural products with anti-obesity effects, a phytochemical investigation of the EtOH extract of the seeds of Momordica cochinchinensis was carried out, which resulted in the isolation of two major triterpenoid saponins: gypsogenin 3-O-β-d-galactopyranosyl(1→2)-[α-l-rhamnopyranosyl (1→3)]-β-d-glucuronopyranoside (1) and quillaic acid 3-O-β-d-galactopyranosyl(1→2)-[α-l-rhamnopyranosyl(1→3)]-β-d-glucuronopyranoside (2). Then, the effects of the isolated triterpenoid saponins (1 and 2) on adipocyte differentiation were evaluated, and it was demonstrated that the isolated saponin (1) showed inhibitory effects on adipogenesis. In mature adipocytes, the isolated saponin (1) reversed tumor necrosis factor α (TNFα)-induced proinflammatory cytokine gene expression. Additionally, the isolated saponin (1) reduced lipolytic gene expression leading to decreased basal lipolysis activity. Collectively, these findings suggest that saponin (1) of M. cochinchinensis exerts beneficial effects in the regulation of adipogenesis and adipocyte inflammation and could be a potential therapeutic alternative in the treatment of obesity-induced metabolic diseases.

No abstract