A potent CBP/p300-Snail interaction inhibitor suppresses tumor growth and metastasis in wild-type p53-expressing cancer

Abstract

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.

Curcumin suppresses the stemness of non‐small cell lung cancer cells via promoting the nuclear‐cytoplasm translocation of TAZ

“…Here, we chose the dosages without affecting the cell viability of NSCLC cells and the nanomole levels of curcumin concentration were use. In addition, the RNA‐sequencing analysis was constructed in this work and it was shown that the Hippo pathway was enriched in cells treated with curcumin, which is different from the previous results showing that the Wnt, JAK2 and Hedgehog pathways are involved in curcumin‐mediated effects on lung cancer cell stemness, 21,22 this difference suggests that curcumin might have several targets or high concentrations of curcumin might have the off‐target effects. Furthermore, we examined the effects of curcumin on the expression of the critical executors (MST1/2, LAST1/2, YAP/TAZ) in Hippo pathway and we found that curcumin just inhibited TAZ expression, but had no effects on the expression of other executors, which means that there are other regulators involved in curcumin‐mediated effects on TAZ activity, such as PIN1, 23 ASK1 24 and BMP‐2 signaling 25 .…”

“…Here, we chose the dosages without affecting the cell viability of NSCLC cells and the nanomole levels of curcumin concentration were use. In addition, the RNA-sequencing analysis was constructed in this work and it was shown that the Hippo pathway was enriched in cells treated with curcumin, which is different from the previous results showing that the Wnt, JAK2 and Hedgehog pathways are involved in curcuminmediated effects on lung cancer cell stemness, 21,22 found that curcumin just inhibited TAZ expression, but had no effects on the expression of other executors, which means that there are other regulators involved in curcumin-mediated effects on TAZ activity, such as PIN1, 23 ASK1 24 and BMP-2 signaling. 25 Consistently, detection on the nucleus and cytoplasmic protein expression showed that curcumin promoted the nuclear-cytoplams translocation of TAZ, but not YAP although they always have the similar functions, this might be resulted by the different structure of YAP and TAZ.…”

“…Although the inhibition of curcumin on the stemness of lung cancer cells was reported before, 21,22 however, the relative higher dosage (Micromol level) was used and the cell viability was also confirmed to be downregulated in these works, thus, the effects of curcumin on the stemness of lung cancer cells might be due to the suppressive effects on the cell viability, which should be excluded. Here, we chose the dosages without affecting the cell viability of NSCLC cells and the nanomole levels of curcumin concentration were use.…”

Targeting the EMT transcription factor Snail overcomes resistance to osimertinib in EGFR‐mutant non‐small cell lung cancer

“…It mainly interfered with the binding of acetyltransferase CBP / P300 with Snail through the binding of CYD19 with Snail protein, which resulted in the loss of acetylation protection of the latter ubiquitination degradation. 33 Unfortunately, these studies were only performed in H1975OR, and not in more EGFR-TKI resistant cell lines. In future, it is hoped that we can further verify these results in more EGFR-TKI cell lines and a PDX model.…”

Epigenetic regulation of intestinal peptide transporter PEPT1 as a potential strategy for colorectal cancer sensitization

“…CREB-binding protein (CBP) and its paralog P300 are histone acetyltransferases capable of acetylating H3K18, H3K27, H3K56, H3K14, and H3K23 27 , 49 . Previous studies have demonstrated that CBP and P300 act as histone acetyltransferase complexes due to their conserved sequence regions 50 , 51 . Some evidence also indicates that CBP and P300 perform unique functions 52 .…”