Combination Treatment of a Phytochemical and a Histone Demethylase Inhibitor—A Novel Approach towards Targeting TGFβ-Induced EMT, Invasion, and Migration in Prostate Cancer

Abstract

Minimizing side effects, overcoming cancer drug resistance, and preventing metastasis of cancer cells are of growing interest in current cancer therapeutics. Phytochemicals are being researched in depth as they are protective to normal cells and have fewer side effects. Hesperetin is a citrus bioflavonoid known to inhibit TGFβ-induced epithelial-to-mesenchymal transition (EMT), migration, and invasion of prostate cancer cells. Targeting epigenetic modifications that cause cancer is another class of upcoming therapeutics, as these changes are reversible. Global H3K27me3 levels have been found to be reduced in invasive prostate adenocarcinomas. Combining a demethylase inhibitor and a known anti-cancer phytochemical is a unique approach to targeting cancer to attain the aforementioned objectives. In the current study, we used an H3K27 demethylase (JMJD3/KDM6B) inhibitor to study its effects on TGFβ-induced EMT in prostate cancer cells. We then gave a combined hesperetin and GSK-J4 treatment to the PC-3 and LNCaP cells. There was a dose-dependent increase in cytotoxicity and inhibition of TGFβ-induced migration and invasion of prostate cancer cells after GSK-J4 treatment. GSK-J4 not only induced trimethylation of H3K27 but also induced the trimethylation of H3K4. Surprisingly, there was a reduction in the H3K9me3 levels. GSK-J4 alone and a combination of hesperetin and GSK-J4 treatment effectively inhibit the important hallmarks of cancer, such as cell proliferation, migration, and invasion, by altering the epigenetic landscape of cancer cells.

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

“… 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. 22 – 25 …”

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

“…This is achieved by downregulating the expression of CCND‐1 by preventing the binding of KDM6B and smad2/3 to the cyclin D1 promoter 48 . A recent study on GSK‐J4 (20 μM) showed that it could inhibit (transforming growth factor beta) TGFβ induced epithelial to mesenchymal transition (EMT), migration and invasion in prostate cancer cells by inhibiting the phosphorylation of smad3 in the LNCaP cells and that of c‐jun in the PC3 cells 49 . GSK‐J4 can thus be considered a promising therapeutic option for prostate cancer.…”

“…KDM6B has been shown to be involved in the development of CRPC, and the combination of MDV3100 and GSK‐J4 is effective against MDV3100‐resistant CRPC as the combination treatment had a higher proliferation inhibition efficiency 48 . Another recently published study showed that a combination of GSK‐J4 with hesperetin inhibited TGFβ induced EMT, migration and invasion in prostate cancer cells by inhibiting the phosphorylation of both smad3 and c‐jun as well as inducing changes in the methylation of H3K4, H3K9 and H3K27 49 . A study on thyroid KRAS‐mutant anaplastic thyroid cancer showed that doxorubicin and GSK‐J4 treatment could significantly increase the inhibition of the proliferation of thyroid cancer cells along with the inhibition of invasion and migration of these cells.…”

“…48 Another recently published study showed that a combination of GSK-J4 with hesperetin inhibited TGFβ induced EMT, migration and invasion in prostate cancer cells by inhibiting the phosphorylation of both smad3 and cjun as well as inducing changes in the methylation of H3K4, H3K9 and H3K27. 49 A study on thyroid KRAS-mutant anaplastic thyroid cancer showed that doxorubicin and GSK-J4 treatment could significantly…”

Enzymes Dysregulation in Cancer: From Diagnosis to Therapeutical Approaches

“…Tests were either performed alone or in combination with phytochemical hesperetin, a citrus bioflavonoid. The researchers found that coupling hesperetin and GSK-J4 treatment at lower doses effectively prevented TGFβ-induced migration and the invasion of the prostate cancer cells, effects that were associated with epigenetic modifications [ 24 ].…”