The inflammatory cytokine IL-6 induces FRA1 deacetylation promoting colorectal cancer stem-like properties

Oncogene
Tingyang WangJimin Shao

Abstract

Colorectal cancer (CRC) has long been known for its tight association with chronic inflammation, thought to play a key role in tumor onset and malignant progression through the modulation of cancer stemness. However, the underlying molecular and cellular mechanisms are still largely elusive. Here we show that the IL-6/STAT3 inflammatory signaling axis induces the deacetylation of FRA1 at the Lys-116 residue located within its DNA-binding domain. The HDAC6 deacetylase underlies this key modification leading to the increase of FRA1 transcriptional activity, the subsequent transactivation of NANOG expression, and the acquisition of stem-like cellular features. As validated in a large (n = 123) CRC cohort, IL-6 secretion was invariably accompanied by increased FRA1 deacetylation at K116 and an overall increase in its protein levels, coincident with malignant progression and poor prognosis. Of note, combined treatment with the conventional cytotoxic drug 5-FU together with Tubastatin A, a HDAC6-specific inhibitor, resulted in a significant in vivo synergistic inhibitory effect on tumor growth through suppression of CRC stemness. Our results reveal a novel transcriptional and posttranslational regulatory cross-talk between inflammati...Continue Reading

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Citations

Oct 16, 2019·Molecular Biology Reports·Xiaoyan JiangSongshu Xiao
Aug 4, 2020·Molecular Oncology·Chelsea Gerada, Kevin M Ryan
Jun 26, 2020·Journal of Research in Medical Sciences : the Official Journal of Isfahan University of Medical Sciences·Davood JafariNima Rezaei
Aug 28, 2020·Frontiers in Immunology·Lia WalcherUta Kossatz-Boehlert
Feb 23, 2021·Oncotarget·Beatrice AraminiKhawaja Husnain Haider
Oct 17, 2020·Journal of Hematology & Oncology·Julia López de AndrésJuan Antonio Marchal
Jan 9, 2022·Journal of Cellular and Molecular Medicine·Xiaobo NieWei-Dong Chen

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Methods Mentioned

BETA
acetylation
enzyme-linked immunosorbent assay
fluorescence-activated cell sorter
FACS
flow cytometry
gene knockout
transfect
co-IP
immunoprecipitation
pull-down

Software Mentioned

GraphPad Prism6
R x64

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