Activation of KRas-ERK1/2 signaling drives the initiation and progression of glioma by suppressing the acetylation of histone H4 at lysine 16
Authors: Zhen Xu
Dongxu Yang
Fang Wang
Yuzhen Wei
Ben Sang
Journal: Life Sciences (2019)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Acetylation of H4 at lysine 16 (H4K16ac); Glioma; KRas-ERK1/2 signaling; Sirt2; TIP60.
Affiliations: Department of Neurosurgery, Jining No.1 People's Hospital, Jining272011, China; Affiliated Jining NO.1 People's Hospital of Jining Medical University, Jining Medical University, Jining272067, China., Department of Pathology, Jining No.1 People's Hospital, Jining272011, China., Department of Neurosurgery, Jining No.1 People's Hospital, Jining272011, China., Department of Neurosurgery, Affiliated Hospital of Jining Medical University, Jining272000, China. Electronic address: .

Abstract:  Background/aims: Acetylation of H4 at lysine 16 (H4K16ac) has been well-characterized as an acetylated mark, and the expression of which is closely associated with the tumorigenesis of human cancers. This study aimed to reveal whether KRas mutation drives the initiation and progression of glioma via modulation of H4 acetylation. Methods: Changes of H4K16 acetylation in human glioblastoma A172 cells following transfection with a plasmid for expression of mutant KRas were tested by western blot analysis. MTT assay, transwell assay, soft-agar colony formation assay, RT-PCR and chromatin immunoprecipitation were carried out to evaluate the effect of H4K16ac on A172 cells growth and migration. Furthermore, the enzymes participating in the deacetylation of H4K16ac were studied by using RT-PCR and western blot analysis. Results: H4K16ac was found to be deacetylated by KRas-ERK1/2 activation. H4K16Q (a plasmid for mimicking H4K16ac) repressed A172 cells viability, colony formation, and migratory capacity. Besides, H4K16ac was capable of regulating the transcription of several ERK1/2 pathway downstream genes. KRas-ERK1/2 signaling repressed H4 acetylation at K16 via modulation of a histone deacetylase Sirt2, as well as a histone acetyl-transferase TIP60. Moreover, KRas-ERK1/2 inhibited TIP60 via an MDM2-dependnet fashion. Conclusion: Our results suggest that activation of KRas-ERK1/2 signaling participates in the onset and progression of glioma at least partially through modulating acetylation of H4 at K16. KRas-ERK1/2 signaling mediates the acetylation of H4K16 via Sirt2 and MDM2-dependnet degeneration of TIP60. 

Retracted: Yes

PubPeer comments:
 This paper belongs to a set of over 400 papers (as per February 2020) that share very similar Western blots with tadpole-like shaped bands, the same background pattern, and striking similarities in title structures, paper layout, bar graph design, and - in a subset - flow cytometry panels. Despite these similarities, these papers are authored by researchers from different departments and institutes, with almost no overlap in authors. The list of these papers is available here: https: docs.google.com spreadsheets d 1KXqTAyl4j-jVorFPMD2XRpr76LcIKJ0CVyIvRj0exYQ edit?usp=sharing A more detailed description of this set of papers, suspected to all be generated by a common source, a paper mill , can be found here: * https: forbetterscience.com 2020 01 24 the-full-service-paper-mill-and-its-chinese-customers (January 2020) * https: scienceintegritydigest.com 2020 02 21 the-tadpole-paper-mill (February 2020) The same paper mill has been described in these papers: * Jana Christopher - Systematic fabrication of scientific images revealed - FEBS Letters (2018) - https: febs.onlinelibrary.wiley.com doi full 10.1002 1873-3468.13201 * Jennifer A Byrne and Jana Christopher - Digital magic, or the dark arts of the 21st centuryu2014how can journals and peer reviewers detect manuscripts and publications from paper mills? - FEBS Letters (2020) - https: febs.onlinelibrary.wiley.com doi full 10.1002 1873-3468.13747 , 
 Retracted [18 June 2020] :  This article has been retracted at the request of the Editor-in-Chief as there are concerns about the reliability of the results included in the article. The journal was initially contacted by the corresponding author to request the retraction as they reported that the colony experimental picture of the U251 cell line is very similar to Fig. 2B in this article, but this article purportedly used the A172 cell line. Moreover, the authors did not find post publication the original data for the A172 colony.  Given the comments of Dr. Elisabeth Bik https: scienceintegritydigest.com 2020 02 21 the-tadpole-paper-mill regarding this article, the journal further requested the author to provide all the raw data. However, the author was not able to fulfil this request. , 
 A [report from the Affiliated Hospital of Jining Medical College] reads as follows (thanks Google Translate): --------------------- 10.  Activation of KRas-ERK1 2 signaling drives the initiation and progression of glioma by suppressing the acetylation of histone H4 at lysine 16 false experiment and false research question by Yang Dongxu of Jining Medical College Affiliated Hospital as the corresponding author. After investigation, the paper  Activation of KRas-ERK1 2 signaling drives the initiation and progression of glioma by suppressing the acetylation of histone H4 at lysine 16 written by Yang Dongxu from the Affiliated Hospital of Jining Medical College as the corresponding author has false experiments and false research issues. The Affiliated Hospital of Jining Medical College will deal with the relevant responsible persons as follows: The corresponding author Yang Dongxu will be (1) ordered to make an in-depth inspection; (2) ordered to withdraw the manuscript of the papers involved; (3) cancel the five-year application for scientific and technological plan projects (special projects, funds, etc.), scientific and technological awards, and titles of scientific and technological talents, etc. Qualification, from March 2, 2020 to March 1, 2025; (4) Cancellation of five-year postgraduate tutor application and appointment qualifications from March 2, 2020 to March 1, 2025 ; (5) Cancellation of three-year professional title promotion qualifications from March 2, 2020 to March 1, 2023; (6) Criticism is reported in the hospital. ,