Abstract C072: Andrographolide exhibits anti-cancer activity via restoring DNMT3B-suppressed ZNF382 expression in pancreatic cancer

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal malignancy. Due to the lack of early diagnosis and the limited response to current clinical treatments, PDAC has a high recurrence rate and a poor 5-year survival rate. Andrographolide, a labdane diterpenoid compound and the main active ingredient found in the medicinal plant Andrographis paniculata, is known for its anti-cancer effects against a variety of cancer types. Nevertheless, there are few studies on the anti-cancer activity and underlying mechanism of andrographolide against PDAC. We recently found that andrographolide suppressed cell viability, proliferation and migration abilities of PDAC cells, as well as impaired tumor growth in vivo. Notably, andrographolide induced the mRNA and protein expression of Zinc finger protein 382 (ZNF382) in PDAC cells. ZNF382 functions as a transcription repressor but its biological function in pancreatic cancer remains unclear. Through analysis of pancreatic adenocarcinoma (PAAD) patient data from TCGA, the expression of ZNF382 is lower in tumor samples than in normal tissues, and patients with higher ZNF382 expression showed better overall survival rates. Recently, we confirmed that ZNF382 expression was significantly decreased in clinical tumor tissues compared with matched normal tissues in 9 out of 10 pancreatic cancer patients. In addition, we demonstrated that overexpression of ZNF382 inhibited malignant phenotypes of PDAC cells and suppressed tumor growth in mice. Based on TCGA database analysis, the ZNF382 promoter is hypermethylated in primary pancreatic tumors, and this hypermethylation pattern correlates with its low expression. We further showed that andrographolide treatment inhibited the expression of DNA methyltransferase 3 beta (DNMT3B) and promoted the demethylation of ZNF382 promoter in PDAC cells. Notably, overexpression of DNMT3B attenuated both the andrographolide-induced expression of ZNF382 and its associated anti-cancer effects. In summary, our findings indicate that ZNF382 serves as a tumor suppressor in pancreatic cancer and suggest that andrographolide exerts its anticancer effects in pancreatic cancer through the suppression of DNMT3B-dependent DNA methylation, leading to the reactivation of ZNF382 expression. Citation Format: Kai-Ru Zhuang, Hsin-Yu Chan, Chian-Feng Chen, Shu-Ling Fu. Andrographolide exhibits anti-cancer activity via restoring DNMT3B-suppressed ZNF382 expression in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C072.