Ibuprofen mediates histone modification to diminish cancer cell stemness properties via a COX2-dependent manner
Authors: Juan Wang
Renle Du
Na Luo
Yonghua Bao
Wenzhi Shen
Xiaoyuan Zhang
Wancai Yang
Wenjuan Gao
Jianjun Li
Journal: British Journal of Cancer (2020)
Discipline: CLINICAL MEDICINE
Keywords: ibuprofen; cancer stemness; histone modification; HDAC; KDM6A/B
Affiliations: Department of Pathology and Institute of Precision Medicine, Jining Medical University, Jining, 272067, China. ., Institute of Breast Research, Jining Medical University, Jining, 272067, China. ., Department of Pathology and Institute of Precision Medicine, Jining Medical University, Jining, 272067, China., Department of Immunology, School of Medicine, Nankai University, Tianjin, 300071, China., Department of Immunology, School of Medicine, Nankai University, Tianjin, 300071, China. .

Abstract:  Background: The anticancer potential of ibuprofen has created a broad interest to explore the clinical benefits of ibuprofen in cancer therapy. However, the current understanding of the molecular mechanisms involved in the anticancer potential of ibuprofen remains limited. Methods: Cancer stemness assays to validate ibuprofen function in vitro and in vivo. Histone modification assays to check the effect of ibuprofen on histone acetylation/methylation, as well as the activity of HDAC and KDM6A/B. Inhibitors' in vivo assays to evaluate therapeutic effects of various inhibitors' combination manners. Results: In our in vitro studies, we report that ibuprofen diminishes cancer cell stemness properties that include reducing the ALDH + subpopulation, side population and sphere formation in three cancer types. In our in vivo studies, we report that ibuprofen decreases tumour growth, metastasis and prolongs survival. In addition, our results showed that ibuprofen inhibits inflammation-related stemness gene expression (especially ICAM3) identified by a high-throughput siRNA platform. In regard to the underlying molecular mechanism of action, we report that ibuprofen reduces HDACs and histone demethylase (KDM6A/B) expression that mediates histone acetylation and methylation, and suppresses gene expression via a COX2-dependent way. In regard to therapeutic strategies, we report that ibuprofen combined HDAC/HDM inhibitors prevents cancer progression in vivo. Conclusions: The aforementioned findings suggest a molecular model that explains how ibuprofen diminishes cancer cell stemness properties. These may provide novel targets for therapeutic strategies involving ibuprofen in the prevention of cancer progression. 

Retracted: No

PubPeer comments:
 In Figure 2n and Figure 4b, two different images of mice have been reused and presented as something else. In Figure 2e, two images of mice are too similar than one would expect. There are some differences, but most of the details of the pattern and shape are identical. ![file] , 
 Four images from Figure 2f seem to have been published again in a different paper where they are described differently. There is at least one common author (WS). Figure 2f, British Journal of Cancer (2020), doi: 10.1038 s41416-020-0906-7, Received: October 22, 2019, https: pubpeer.com publications A88FEF281AABB45674E6CF508F6BC9 Figure 2F, Stem Cell Research Therapy (2020), doi: 10.1186 s13287-020-01884-4, Received: December 7, 2019, https: pubpeer.com publications 80FE8CA2ADFDCFE7BDB78213647819 *** ![file] , 
 Thank you for your pointing this out. We are very sorry for these mistakes. At first, we performed aspirin and ibuprofen to diminish cancer cell stemness at the same time, CCL16 and other genes we selected may work as the potential target genes of aspirin and ibuprofen. Overall itu2019s one story at first. However, unsufficient evidence caused the story was not be published. We have to separate these data as u2018aspirin diminishesu2026u2019 u2018ibuprofen diminishesu2026u2019 by some authors. Some data maybe disordered unintentionally. The next question we meted was the software, especially the living image processing, we first adjust the same color range, then pasted to PPT and combined pasted to Illustrator. Some of them were changed and became the same. We asked for help and were answered some software were trial version. Most importantly, it was my fault that I didnu2019t check the data carefully as the vital author. Under pressure of many times submissions, I neglect my duty that I didnu2019t check the data carefully. Anyway, we apologized for the mistakes and thanks again for your comments. We will apply for correction for these mistakes if the editor was approved. ,