Article ; Online: Small molecule JQ1 promotes prostate cancer invasion via BET-independent inactivation of FOXA1.
The Journal of clinical investigation
2020 Volume 130, Issue 4, Page(s) 1782–1792
Abstract: Recent findings have shown that inhibitors targeting bromodomain and extraterminal domain (BET) proteins, such as the small molecule JQ1, are potent growth inhibitors of many cancers and hold promise for cancer therapy. However, some reports have also ... ...
| Abstract | Recent findings have shown that inhibitors targeting bromodomain and extraterminal domain (BET) proteins, such as the small molecule JQ1, are potent growth inhibitors of many cancers and hold promise for cancer therapy. However, some reports have also revealed that JQ1 can activate additional oncogenic pathways and may affect epithelial-to-mesenchymal transition (EMT). Therefore, it is important to address the potential unexpected effect of JQ1 treatment, such as cell invasion and metastasis. Here, we showed that in prostate cancer, JQ1 inhibited cancer cell growth but promoted invasion and metastasis in a BET protein-independent manner. Multiple invasion pathways including EMT, bone morphogenetic protein (BMP) signaling, chemokine signaling, and focal adhesion were activated by JQ1 to promote invasion. Notably, JQ1 induced upregulation of invasion genes through inhibition of Forkhead box protein A1 (FOXA1), an invasion suppressor in prostate cancer. JQ1 directly interacted with FOXA1 and inactivated FOXA1 binding to its interacting repressors TLE3, HDAC7, and NFIC, thereby blocking FOXA1-repressive function and activating the invasion genes. Our findings indicate that JQ1 has an unexpected effect of promoting invasion in prostate cancer. Thus, the ill effect of JQ1 or its derived therapeutic agents cannot be ignored during cancer treatment, especially in FOXA1-related cancers. |
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| MeSH term(s) | Animals ; Azepines/pharmacology ; Epithelial-Mesenchymal Transition/drug effects ; Hepatocyte Nuclear Factor 3-alpha/metabolism ; Humans ; Male ; Mice ; Mice, SCID ; Neoplasm Invasiveness ; Neoplasm Proteins/metabolism ; PC-3 Cells ; Prostatic Neoplasms/drug therapy ; Prostatic Neoplasms/metabolism ; Prostatic Neoplasms/pathology ; Proteins/metabolism ; Triazoles/pharmacology ; Xenograft Model Antitumor Assays |
| Chemical Substances | (+)-JQ1 compound ; Azepines ; FOXA1 protein, human ; Hepatocyte Nuclear Factor 3-alpha ; Neoplasm Proteins ; Proteins ; Triazoles ; bromodomain and extra-terminal domain protein, human |
| Language | English |
| Publishing date | 2020-01-10 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 3067-3 |
| ISSN | 1558-8238 ; 0021-9738 |
| ISSN (online) | 1558-8238 |
| ISSN | 0021-9738 |
| DOI | 10.1172/JCI126327 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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