Abstract
Bromodomain-containing protein 4 (BRD4) is a potential therapeutic target of skin squamous cell carcinoma (SCC). I-BET726 is a novel BRD4 inhibitor. Its potential effect in skin SCC cells was tested in the present study. We show that I-BET726 potently inhibited survival, proliferation, cell cycle progression, and migration in established (A431/SCC-9/SCC-12/SCC-13 lines) and primary human skin SCC cells. I-BET726 induced significant apoptosis activation in skin SCC cells. It was more efficient in inhibiting skin SCC cells than known BRD4 inhibitors (JQ1, CPI203, and AZD5153). I-BET726 not only downregulated BRD4-regulated proteins (c-Myc, Bcl-2, and cyclin D1), but also inhibited sphingosine kinase 1 (SphK1) and Akt signalings in SCC cells. Restoring Akt activation, by a constitutively active S473D mutant Akt1 (“caAkt1”), partially inhibited I-BET726-induced cytotoxicity in A431 cells. In vivo, I-BET726 oral administration potently inhibited A431 xenograft growth in severe combined immunodeficient mice. Downregulation of BRD4-regulated proteins and inhibition of the SphK1-Akt signaling were detected in I-BET726-treated A431 xenograft tumor tissues. Together, I-BET726 inhibits skin SCC cell growth in vitro and in vivo.
Highlights
Skin squamous cell carcinoma (SCC) causes significant cancer-related human mortalities[1,2,3]
I-BET726 dose-dependently decreased the number of A431 cell colonies (Fig. 1b) and BrdU enzyme-linked immunosorbent assay (ELISA) OD (Fig. 1c), indicating an antiproliferative activity by IBET726
When analyzing cell cycle progression, we show that I-BET726 (50 nM) disrupted cell cycle progression, causing G1–S arrest in A431 cells (Fig. 1e)
Summary
Skin squamous cell carcinoma (SCC) causes significant cancer-related human mortalities[1,2,3]. Bromodomain and extraterminal (BET) family proteins have emerged as exciting and novel therapeutic proteins for cancer[4,5]. Bromodomain-containing protein 4 (BRD4) is the most studied and a primary member of BET family. BRD4 overexpression and/or hyperactivation is associated with tumorigenesis of hematological and solid tumors[4,5]. BRD4 regulates transcription elongation of key genes of Reversely, forced overexpression of BRD4 facilitated skin SCC cell proliferation[6]. These results suggest that targeting BRD4 could be a novel and efficient strategy against skin SCC cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
