Effects of GSK-J4 on JMJD3 Histone Demethylase in Mouse Prostate Cancer Xenografts

Abstract

Background/Aim: Histone methylation status is required to control gene expression. H3K27me3 is an epigenetic tri-methylation modification to histone H3 controlled by the demethylase JMJD3. JMJD3 is dysregulated in a wide range of cancers and has been shown to control the expression of a specific growth-modulatory gene signature, making it an interesting candidate to better understand prostate tumor progression in vivo. This study aimed to identify the impact of JMJD3 inhibition by its inhibitor, GSK4, on prostate tumor growth in vivo. Materials and Methods: Prostate cancer cell lines were implanted into Balb/c nude male mice. The effects of the selective JMJD3 inhibitor GSK-J4 on tumor growth were analyzed by bioluminescence assays and H3K27me3-regulated changes in gene expression were analyzed by ChIP-qPCR and RT-qPCR. Results: JMJD3 inhibition contributed to an increase in tumor growth in androgen-independent (AR-) xenografts and a decrease in androgen-dependent (AR+). GSK-J4 treatment modulated H3K27me3 enrichment on the gene panel in DU-145-luc xenografts while it had little effect on PC3-luc and no effect onLNCaP-luc. Effects of JMJD3 inhibition affected the panel gene expression. Conclusion: JMJD3 has a differential effect in prostate tumor progression according to AR status. Our results suggest that JMJD3 is able to play a role independently of its demethylase function in androgenindependent prostate cancer. The effects of GSK-J4 on AR+ prostate xenografts led to a decrease in tumor growth.

Antitumoral Potential of the Histone Demethylase Inhibitor GSK-J4 in Retinoblastoma

“…GSK-J4, a selective inhibitor of KDM6A/B, which are usually aberrantly expressed in cancers, has been found to have significant antitumor efficacy in several cancers. 26 , 30 , 42 , 43 However, the roles of GSK-J4 in retinoblastoma remain unclear. In the present study, we performed CCK-8, EdU incorporation and colony formation assays and found that GSK-J4 obviously inhibited the proliferation of retinoblastoma cells in a concentration- and time-dependent manner.…”

“… 46 In addition, in vivo studies also showed the suitable tolerance of GSK-J4 in mice. 26 , 29 , 30 Moreover, some studies have indicated that GSK-J4 could enhance the effectiveness of known anticancer drugs when used in combination. 33 , 43 , 58 Although promising, these results are still preliminary, and further investigations involving more extensive research and clinical trials will be considered soon, similar to other strategies targeting the regulation of H3K27me3, such as PRC2 inhibitors, which have been well studied and entered multiple clinical trials.…”

“…The utilization of PRC2 inhibitors has been extensively investigated in various cancer models, and several of these inhibitors are currently under clinical evaluation. 22 – 25 In contrast, research on KDM6 inhibitors has only recently been conducted in some cancers, such as prostate tumors, neuroblastoma, head and neck cancer, and colorectal cancer, 26 – 29 and most of these inhibitors have shown promising prospects for cancer treatment. However, the effect of KDM6 inhibition on retinoblastoma is still unclear, and the biological functions and molecular mechanisms of KDM6 inhibitors in retinoblastoma remain to be elucidated.…”

GSK‐J4: An H3K27 histone demethylase inhibitor, as a potential anti‐cancer agent

“…GSK‐J4 also increased the sensitivity of chemoresistant CRC cells to oxaliplatin by reducing the tumor growth rate 50 . A study involving androgen‐positive (AR+) prostate xenografts in mice showed that GSK‐J4 reduced tumor growth in AR+ xenografts, whereas there was no significant effect on AR‐ xenografts 51 …”

“…50 A study involving androgenpositive (AR+) prostate xenografts in mice showed that GSK-J4 reduced tumor growth in AR+ xenografts, whereas there was no significant effect on AR-xenografts. 51…”