BET inhibitor suppresses melanoma progression via the noncanonical NF-κB/SPP1 pathway

Abstract

Background: Bromodomain and extra-terminal domain (BET) inhibitors have shown profound efficacy against hematologic malignancies and solid tumors in preclinical studies. However, the underlying molecular mechanism in melanoma is not well understood. Here we identified secreted phosphoprotein 1 (SPP1) as a melanoma driver and a crucial target of BET inhibitors in melanoma. Methods: Bioinformatics analysis and meta-analysis were used to evaluate the SPP1 expression in normal tissues, primary melanoma, and metastatic melanoma. Real-time PCR (RT-PCR) and Western blotting were employed to quantify SPP1 expression in melanoma cells and tissues. Cell proliferation, wound healing, and Transwell assays were carried out to evaluate the effects of SPP1 and BET inhibitors in melanoma cells in vitro . A xenograft mouse model was used to investigate the effect of SPP1 and BET inhibitors on melanoma in vivo . Chromatin immunoprecipitation (ChIP) assay was performed to evaluate the regulatory mechanism of BET inhibitors on SPP1. Results: SPP1 was identified as a melanoma driver by bioinformatics analysis, and meta-analysis determined it to be a diagnostic and prognostic biomarker for melanoma. SPP1 overexpression was associated with poor melanoma prognosis, and silencing SPP1 suppressed melanoma cell proliferation, migration, and invasion. Through a pilot drug screen, we identified BET inhibitors as ideal therapeutic agents that suppressed SPP1 expression. Also, SPP1 overexpression could partially reverse the suppressive effect of BET inhibitors on melanoma. We further demonstrated that bromodomain-containing 4 (BRD4) regulated SPP1 expression. Notably, BRD4 did not bind directly to the SPP1 promoter but regulated SPP1 expression through NFKB2. Silencing of NFKB2 resembled the phenotype of BET inhibitors treatment and SPP1 silencing in melanoma. Conclusion: Our findings highlight SPP1 as an essential target of BET inhibitors and provide a novel mechanism by which BET inhibitors suppress melanoma progression via the noncanonical NF-κB/SPP1 pathway.

The BRD9/7 Inhibitor TP-472 Blocks Melanoma Tumor Growth by Suppressing ECM-Mediated Oncogenic Signaling and Inducing Apoptosis

“…Inhibitors targeting EZH2 also induce the re-expression of tumor suppressors associated with enhanced patient survival [ 17 ]. Past studies have also revealed that JQ1 can be used to treat vemurafenib-resistant melanoma cells [ 18 ] and that BET inhibitors effectively suppress melanoma progression via the noncanonical NF-κB/SPP1 pathway [ 19 ]. However, information regarding the role of TP-472 in melanoma therapy remains limited.…”

“…Additionally, PAT-1251 (newly designated GB2064), which targets LOXL2, has been used in phase 1 clinical trials for the treatment of lung disease as well as metastatic breast cancer [ 48 , 49 ]. Studies have also shown that SPP1 is an important target of BET inhibitors, which can effectively inhibit the growth of melanoma cells [ 19 ]. A recent study identified CA-074Me as a specific cell-permeable CTSB inhibitor [ 50 ] and small-molecule inhibitor diethyl-pythiDC that targets P4HA1 has been used for treating colorectal cancer [ 51 ].…”

Bromodomain Inhibition Attenuates the Progression and Sensitizes the Chemosensitivity of Osteosarcoma by Repressing GP130/STAT3 Signaling

“…The ability of BET inhibitor targeting oncogenic pathways in different cancers endows its extensive clinical applications, and increasing number of FDA-approved BET inhibitors have been studied in variety of cancers (31)(32)(33). In our previous studies, we explored the ability of a potent BRD4 inhibitor NHWD-870 shows great tumor suppressive potential in multiple solid tumors by depleting phosphorylated BRD4 and c-MYC (8,9). In the current study, we further explored the anti-osteosarcoma activity of NHWD-870 and the related mechanisms.…”

“…The significant clinical value of BET targeted therapy has been proven, and several BET inhibitors have been designed and applied ( 5 – 7 ). In our previous study, we reported the discovery and characterization of the novel BET inhibitor NHWD-870, and mechanism by which BRD4 inhibition suppresses tumor growth ( 8 , 9 ). The present study aimed to further explore the effects of NHWD-870 in osteosarcoma and the related mechanism.…”

Interrogating Epigenome toward Personalized Approach in Cutaneous Melanoma

“…So far, several BETis, such as thienodiazepine JQ1, I-BET151/GSK1210151A, I-BET762/GSK525762, ABBV-075, PLX51107, ODM-207, and ZEN003694 have shown encouraging clinical outcomes with tolerable toxicity and increased efficiency in various tumor types [ 260 , 261 ]. BRD4 is a notorious BET family member that is consistently reported to be amplified or overexpressed in human melanoma lines and primary tumors [ 262 ]. Notably, one study suggested that BETi treatments significantly affected melanoma cell proliferation in vitro and tumor growth and metastasis in vivo due to the downregulation of genes involved in cell cycle progression (SKP2, ERK1, and c-MYC) and concomitant accumulation of cyclin-dependent kinase inhibitors (p21 and p27).…”