BET bromodomain inhibitor JQ1 decreases CD30 and CCR4 expression and proliferation of cutaneous T-cell lymphoma cell lines

Abstract

Bromodomain and external domain (BET) proteins regulate cell growth, proliferation, cell cycle, and differentiation in various cancers. Therefore, they have emerged as interesting targets. The effect of BET inhibitor on cutaneous T-cell lymphoma (CTCL), however, is yet to be known. Here, we examined the effect of BET inhibitor JQ1 on four cell lines (MyLa, SeAx, Hut78 and HH cells). CTCL cell lines were treated with JQ1 and cell number, cell cycle, frequency of apoptosis, and expressions of CD25, CD30 and CCR4 on the cell surface were evaluated by flow cytometry. Cell surface molecules were also analyzed by quantitative RT-PCR. JQ1 dose-dependently decreased the cell number of CTCL cells through G1 arrest concomitantly with downregulation of c-Myc expression. JQ1 induced senescence in MyLa cells and apoptosis in Hut78 and HH cells. We also showed that JQ1 inhibited tumor growth of HH cells in vivo. Moreover, JQ1 downregulated CD30 and CCR4 expression both on the cell surface and at mRNA levels. Thus, BET bromodomain inhibitor JQ1 may be useful for treatment of CTCL.

Preclinical Studies Support Combined Inhibition of BET Family Proteins and Histone Deacetylases as Epigenetic Therapy for Cutaneous T-Cell Lymphoma

“…Our findings show similar effects specifically for CTCL. Another study demonstrated that JQ1 can decrease CTCL cell proliferation as well as CD30 and CCR4 expression [33]. Based on these studies and our current data, it is likely that HDACi exert dominant effects on CTCL cell differentiation and apoptosis, while BETi and HDACi both block proliferative drivers of CTCL growth, thereby exerting synergistic beneficial effects when used in combination.…”

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

“…Kim et al showed that the cytotoxic effects induced by BETi (such as JQ1 42 or ABBV‐075 43 ) resulted synergistically amplified by either HDACi (vorinostat 3 or romidepsin 4 ) or BCL2i (venetoclax 44 ) (Combination J, Figure ) in the majority of both CTCL cell lines (MyLa, Sez4, HH, and Hut78) and CTCL tumor samples derived from patients who had previously tried both single and multiple therapies without success. In this study, synergistic effects on the modulation of the genes BCL2 and MYC, and of genes encoding for proapoptotic and cell cycle regulation factors (BIM, CDKN1A , and p21 ) , as well as a lower level of BCL2L1 expression were observed .…”

“…In the same system, the treatment with JQ1 42 alone was able to induce cell cycle arrest but only limited apoptosis. At a molecular level, in UC cells the JQ1 42 /romidepsin 4 combination increased H3K27 acetylation but decreased H3K4 trimethylation, downregulating antiapoptotic and oncogenic factors such as survivin, BCL‐2, BCL‐XL, c‐MYC, EZH2, and SKP2 and diminishing AKT phosphorylation …”

Bromodomain‐containing protein 4 inhibition alleviates matrix degradation by enhancing autophagy and suppressing NLRP3 inflammasome activity in NP cells

“…Melatonin has been reported to inhibit NP cell proliferation and matrix remodeling, while ERRFI1 has been found to inhibit proliferation and alleviate inflammation of NP cells (Guo et al, 2019;Li et al, 2017). Numerous reports have revealed that BRD4 promotes cell proliferation in gastric cancer and cutaneous T-cell lymphoma (Ba et al, 2018;Dong, Hu, Chen, Hu, & Chen, 2018;Kamijo et al, 2017;. Herein, the CCK-8 and flow cytometry results revealed that JQ1 inhibited proliferation by inducing cell cycle Autophagy is increased in the pathological process of IDD and alleviates the matrix catabolism induced by TNF-α and IL-1β (Gruber, Hoelscher, Ingram, Bethea, & Hanley, 2015;Li et al, 2018;Xu et al, 2015;Ye et al, 2011;Ye et al, 2013).…”