Biological and molecular effects of bromodomain and extra‐terminal (BET) inhibitors JQ1, IBET‐151, and IBET‐762 in OSCC cells

Abstract

Background Despite improvements in oral squamous cell carcinoma (OSCC) management, survival rates remain relatively low and novel anti‐neoplastic agents are needed. Bromodomain and extra‐terminal (BET) inhibitors proved to be promising agents for cancer treatment. We investigated the effects of three BET inhibitors (JQ1, IBET‐151, IBET‐762) on SCC‐25 cell line and primary oral cancer cell culture. Methods Cell viability was evaluated by MTT. Protein levels of MCM5 and cleaved‐PARP were estimated by Western blot. Clonogenic and migratory abilities were determined by colony forming and scratch assays. BET inhibitors effects on mRNA levels of E‐Cadherin, Vimentin, SNAI1, SNAI2, CLU, SERPINI1, MCM5, c‐Myc, E2F, IL7R, and PPARg were analyzed by qPCR. Results BET inhibitors significantly reduced oral cancer cell viability. JQ1 showed the greatest effect reducing cell viability to 10%, both in SCC‐25 and primary OSCC cultures (P < 0.001), compared to control cells. Cells treated with BET inhibitors displayed a reduction to 50% in colony forming capacity compared to control cells (P < 0.0001) and the colonies were smaller; they also had a 50%‐60% reduction in migratory capacity (P < 0.05) compared to untreated cells. BET inhibitors had a significant impact on genes related to epithelial to mesenchymal transition and other cancer cell markers, notably on MCM5, a gene related to cell cycle control. Conclusions BET inhibitors induce both OSCC cell death and reduction of tumor aggressiveness. Molecular mechanisms of BET inhibition involve among others, MCM5 downregulation. Importantly, this study demonstrates for the first time the anti‐tumoral effect of IBET‐151 and IBET‐762 in oral cancer.

Inhibitors of bromodomain and extra‐terminal proteins for treating multiple human diseases

“…The greatest number of currently available BETi belong to the noncovalent BETi class, which form monovalent interactions with individual BET BDs. Description of the first noncovalent BETi, JQ1 157 has lead the way for IBET‐762, IBET‐151, OTX015, ZEN‐3694, and many others 1,55 . These BETi are commonly known for their ability to elicit antitumor activity in cancer cell lines as well as various murine cancer models 57,58,158–160 .…”

“…The chemical structure of pan‐BETi JQ1, for example, allows for interactions with residues in the ZA‐ and BC‐loops of both BD1 and BD2 77,157 . There are many pan‐BETi currently available, such as JQ1, I‐BET151, ZEN‐3694, many of which are under clinical investigation for the treatment of cancer 1,3,26,31,34,48,52,59,165–200 …”

“…Evidence is mounting to support the use of BETi in treating cancer, metabolic, inflammatory, neurologic, cardiovascular, and musculoskeletal diseases. [1][2][3]14,19,20,29,31,44,[50][51][52][53][54][55][56][57][58][59][60][61][62] Investigation of BETi potential as an antiviral has also recently garnered interest. [63][64][65][66][67] Unlike other reviews in the field, we focus this review on explaining why targeting BET proteins shows potential benefit in seemingly unrelated disease states.…”

Hippo Pathway and YAP Signaling Alterations in Squamous Cancer of the Head and Neck

“…Given that the PI3K-PDK1 axis mediates YAP/TAZ activation by different stimuli (EGFR, FAK, fibronectin, GPCRs) and that alterations in the PIK3CA gene are frequent events in HNSCCs and are associated with YAP transcriptional activation and poor outcome [24], specific PI3K inhibitors should be evaluated. Recently, inhibitors of the bromodomain and extra-terminal domain (BET) family of proteins (BRD1-4) have shown successful results in the treatment of HNSCC, including tumor models resistant to Cetuximab [124][125][126]. This brings HNSCC therapeutic options into the thriving field of epigenetics.…”

Epigenetic treatment combinations to effectively target cisplatin‐resistant germ cell tumors: past, present, and future considerations

“…They are the only domains, which bind specifically to histone acetylation marks (Jain & Barton, 2017). Recently, the anti-cancer efficacy of inhibitors against the bromodomain and extra-terminal domain-containing (BET) protein family have been evaluated in several cancers, such as prostate, breast, colon, intestine, pancreas, liver, lung, brain, oral squamous cell carcinoma, and leukemias (Sahai et al, 2016;Saenz et al, 2017;Xu & Vakoc, 2017;Sahni & Keri, 2018;Zhang et al, 2018;Baldan et al, 2019). Even though combined treatment with HDAC and BET inhibitors (BETi) revealed additive or synergistic effects in several cancer entities, such as cutaneous T-cell lymphoma, neuroblastoma, glioblastoma, non-small cell lung cancer, adenocarcinoma, and colon cancer (Mazur et al, 2015;Shahbazi et al, 2016;Adeegbe et al, 2017;Meng et al, 2018;Rajendran et al, 2019;Zhao et al, 2019), so far only few studies described the mono-and combined treatment options with BETis in GCTs.…”