Use of anthracyclines such as doxorubicin (DOX), for the treatment of cancer, is known to induce cardiotoxicity, begetting numerous evaluations of this adverse effect. This review emphasizes the mechanism of how consideration of DOX-induced cardiotoxicity is important for the development of cardioprotective agents. As DOX is involved in mitochondrial dysfunction, enzymes involved in epigenetic modifications that use mitochondrial metabolite as substrate are most likely to be affected. Therefore, this review article focuses on the fact that epigenetic modifications, namely, DNA methylation, histone modifications, and noncoding RNA expression, contribute to DOX-associated cardiotoxicity. Early interventions needed for patients undergoing chemotherapy, to treat or prevent heart failure, would, overall, improve the survival, and quality of life of cancer patients. These epigenetic modifications can either be used as molecular markers for cancer prognosis or represent molecular targets to attenuate DOX-induced cardiotoxicity in cancer patients.

Gastric cancer is one of the leading causes of cancer death worldwide. Previous studies demonstrated that activation of STAT3 is crucial for the development and progression of gastric cancer. However, the role of STAT3 in neuronal related gene methylation in gastric cancer has never been explored. In this study, by using DNA methylation microarray, we identified a potential STAT3 target, C11orf87, showing promoter hypomethylation in gastric cancer patients with lower STAT3 activation and AGS gastric cancer cell lines depleted with STAT3 activation. Although C11orf87 methylation is independent of its expression, ectopic expression of a constitutive activated STAT3 mutant upregulated its expression in gastric cancer cell line. Further bisulfite pyrosequencing demonstrated a progressive increase in DNA methylation of this target in patient tissues from gastritis, intestinal metaplasia, to gastric cancer. Intriguingly, patients with higher C11orf87 methylation was associated with better survival. Furthermore, hypermethylation of C11orf87 was also frequently observed in other GI cancers, as compared to their adjacent normal tissues. These results suggested that C11orf87 methylation may serve as a biomarker for diagnosis and prognosis of GI cancers, including gastric cancer. We further postulated that constitutive activation of STAT3 might be able to epigenetically silence C11orf87 as a possible negative feedback mechanism to protect the cells from the overactivation of STAT3. Targeted inhibition of STAT3 may not be appropriate in gastric cancer patients with promoter hypermethylation of C11orf87.

Bladder cancer is one of the most common occurring cancers in urothelial carcinoma. The previous study suggested that cancer cells undergo immunoevasion due to epigenetic silencing of NKG2DL, in which NKG2D-NKG2DL interaction induced natural killer (NK) cell-mediated cytotoxicity. We hypothesized that NK-mediated cytotoxicity can be reactivated by restoring the expression of NKG2DL on tumor cells. Our previous studies demonstrated that cyproheptadine (CPH) is a novel HDAC inhibitor exhibiting antitumor activity by cell cycle arrest and apoptosis. To understand the mechanism behind, RNA-seq showed an upregulation of ULBP2, a NKG2DL, in bladder cancer cells treated with CPH. Interestingly, upregulation of ULBP2, was accompanied with the enrichment of H3K27Ac and H3K4me3 at ULBP2 promoter, was observed in cells treated with CPH. Increased NK-specific lysis was observed in CPH-treated cells co-cultured with NK-92 cells. More importantly, treatment of CPH enhanced the efficacy of immune checkpoint inhibitor in a syngeneic mice bladder cancer model. In conclusion, our results suggested that CPH may be a novel HDAC inhibitor which may elicit immune response in NK-cell dependent manner. Citation Format: Himani Kumari, Guan-Ling Lin, Chih-Chieh Yeh, Ciao-Ni Chen, Yu-Ming Chuang, Wan-Hong Huang, Wen-Long Huang, Steven Lin, Michael W. Chan. Effects of cyproheptadine in eliciting natural killer cell-mediated immune response in bladder cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4166.