Abstract
BIX-01294, an euchromatic histone-lysine N-methyltransferase 2 (EHMT2) inhibitor, has been reported to induce apoptosis in human neuroblastoma cells and inhibit the proliferation of bladder cancer cells. However, the definite mechanism of the apoptosis mediated by BIX-01294 in bladder cancer cells remains unclear. In the present study, we found that BIX-01294 induced caspase-dependent apoptosis in human bladder cancer cells. Moreover, our data show BIX-01294 stimulates endoplasmic reticulum stress (ER stress) and up-regulated expression of PMAIP1 through DDIT3 up-regulation. Furthermore, down-regulation of the deubiquitinase USP9X by BIX-01294 results in downstream reduction of MCL1 expression, leading to apoptosis eventually. Thus, our findings demonstrate PMAIP1-USP9X-MCL1 axis may contribute to BIX-01294-induced apoptosis in human bladder cancer cells.
Highlights
euchromatic histone-lysine N-methyltransferase 2 (EHMT2), known as G9a, is an important enzyme for histone H3 dimethylation at lysine-9 [1,2]
Western blot analysis demonstrates that BIX-01294 (0, 5, 10 μmol/l) significantly activated CASP8, CASP9, CASP3 and cleaved the substrate of CASP3, PARP1 in bladder cancer cells treated for 24 hours (Figure 1B)
To characterize whether the apoptosis induced by BIX-01294 is related to EHMT2, we treated cells with BIX-01294 after the cells were transfected with EHMT2 small interfering RNA (siRNA)
Summary
EHMT2, known as G9a, is an important enzyme for histone H3 dimethylation at lysine-9 [1,2]. EHMT2 is overexpressed in breast, prostate, colon, bladder, ovarian, melanoma, lung, and liver cancers [3,4,5]. Recent research shows that enhanced expression of EHMT2 is involved in the proliferation of cancer cells [6]. BIX-01294 can induce apoptosis in human neuroblastoma cells by raising CASP8 and CASP3 activity [9]. BIX-01294 can decrease the proliferating activity of bladder cancer cells [6]. It was reported that knockdown of EHMT2 by siRNA [3,4,10,11] or treatment with BIX-01294 [10,12,13] inhibited growth of bladder, lung, prostate, and breast cancer cells
Sign-in/Register to view highlights & summary 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.
