Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Aug 15, 2019; 11(8): 599-621
Published online Aug 15, 2019. doi: 10.4251/wjgo.v11.i8.599
KMT2D deficiency enhances the anti-cancer activity of L48H37 in pancreatic ductal adenocarcinoma
Si-Si Li, Wei-Liang Jiang, Wen-Qin Xiao, Kai Li, Ye-Fei Zhang, Xing-Ya Guo, Yi-Qi Dai, Qiu-Yan Zhao, Ming-Jie Jiang, Zhan-Jun Lu, Rong Wan
Si-Si Li, Wei-Liang Jiang, Wen-Qin Xiao, Kai Li, Ye-Fei Zhang, Xing-Ya Guo, Yi-Qi Dai, Qiu-Yan Zhao, Zhan-Jun Lu, Rong Wan, Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
Si-Si Li, Qiu-Yan Zhao, Ming-Jie Jiang, Rong Wan, Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China

Author contributions: Li SS and Wan R contributed equally to this work; Li SS and Wan R designed the research; Li SS, Jiang WL, Xiao WQ, Zhang YF, Guo XY and Dai YQ performed the research; Li SS, Jiang WL, Li K and Xiao WQ contributed to the analytic tools; Zhao QY, Jiang MJ and Lu ZJ provided the clinical specimen and reagents; Li SS wrote the paper.
Institutional review board statement: All patients participated in this study gave their informed consent. Institutional review board approval of our hospital was obtained for this study. Colleague Ming-Jie Jiang provided human pancreatic cancer tissue specimens in our study.
Institutional animal care and use committee statement: All animal experiments were in line with the Shanghai Jiao Tong University's Policy on the Care and Use of Laboratory Animals.
Conflict-of-interest statement: There is no conflict of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Rong Wan, PhD, Chief Doctor, Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 100 Haining Road, Hongkou District, Shanghai 201620, China.
Telephone: +86-21-63240090 Fax: +86-21-63241377
Received: October 22, 2018
Peer-review started: October 23, 2018
First decision: November 27, 2018
Revised: January 23, 2019
Accepted: February 27, 2019
Article in press: February 27, 2019
Published online: August 15, 2019
Research background

Pancreatic ductal adenocarcinoma is a kind of refractory disease with high mortality. Novel therapeutic strategies are urgently needed for patients with advanced pancreatic cancer.

Research motivation

Recent findings showed the predictive and therapeutic value of targeting lysine methylation signaling in pancreatic ductal adenocarcinoma (PDAC). L48H37, a novel curcumin analog, which potentially acts on histone-lysine N-methyltransferase 2D. The relationship between these two factors in the treatment of pancreatic cancer remains unknown, and the answer to this question gives significant insight into the additional ways in which these interventions work and may improve treatment efficacy.

Research objectives

To determine the anti-cancer effect of L48H37 alone and combined with KMT2D deficiency in PDAC. L48H37 turned out to have better efficacy in anti-pancreatic cancer in the absence of KMT2D. Targeting histone methyltransferase in combination with chemotherapy provides a new direction for cancer treatment.

Research methods

In vitro, the viability and proliferation of PDAC cell lines were determined by CCK8 and colony formation assay. Apoptosis, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) levels and cell cycle profile were investigated by flow cytometry methods. Migration was assessed by the wound healing assay. The protein and mRNA levels of relevant factors in cells or tissues were analyzed by immunologic- and molecular-based assays. In vivo tumor xenografts were also established. In addition, a bioinformatics prediction was run throughout this entire study.

Research results

L48H37 inhibited proliferation and induced apoptosis in SW1990 and ASPC-1 cells in a dose- and time-dependent manner, while also reducing MMP, increasing ROS levels, arresting cell cycle at the G2/M stages and activating the ER stress pathway. Silencing KMT2D significantly augmented L48H37-induced apoptosis and the ER stress pathway. Targeting KMT2D in combination with L48H37 remarkably reduced tumor loading in nude mice. The differentially expressed genes in KMT2D-deficient PDAC cell lines were functionally categorized into the extrinsic apoptotic signaling pathway. However, in contrast to other research, there is no evidence that KMT2D expression level is related to prognosis. The key target of KMT2D deficiency for treatment remains to be studied.

Research conclusions

We report here for the first time that L48H37 exerts a potent anti-cancer effect in PDAC, which is augmented by KMT2D deficiency. These results pave the way for the combined application of targeting epigenetic therapy and chemotherapy.

Research perspectives

Our findings provide new insights into targeting histone methyltransferases in combination with chemotherapy in order to improve the efficacy of the latter.