Novel chemokine-like activities of histones in tumor metastasis

Oncotarget. 2016 Sep 20;7(38):61728-61740. doi: 10.18632/oncotarget.11226.


Histones are intracellular nucleosomal components and extracellular damage-associated molecular pattern molecules that modulate chromatin remodeling, as well as the immune response. However, their extracellular roles in cell migration and invasion remain undefined. Here, we demonstrate that histones are novel regulators of tumor metastasis with chemokine-like activities. Indeed, exogenous histones promote both hepatocellular carcinoma (HCC) cell migration and invasion through toll-like receptor (TLR)4, but not TLR2 or the receptor for advanced glycosylation end product. TLR4-mediated activation of nuclear factor-κB (NF-κB) by extracellular signal-regulated kinase (ERK) is required for histone-induced chemokine (e.g., C-C motif ligand 9/10) production. Pharmacological and genetic inhibition of TLR4-ERK-NF-κB signaling impairs histone-induced chemokine production and HCC cell migration. Additionally, TLR4 depletion (by using TLR4-/- mice and TLR4-shRNA) or inhibition of histone release/activity (by administration of heparin and H3 neutralizing antibody) attenuates lung metastasis of HCC cells injected via the tail vein of mice. Thus, histones promote tumor metastasis of HCC cells through the TLR4-NF-κB pathway and represent novel targets for treating patients with HCC.

Keywords: NF-κB; TLR4; hepatocellular carcinoma; histone; metastasis.

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / metabolism
  • Cell Line, Tumor
  • Cell Movement
  • Chemokines / metabolism*
  • Chromatin / chemistry
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Glycosylation
  • Histones / metabolism*
  • Immune System
  • Liver Neoplasms / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neoplasm Transplantation
  • Nucleosomes / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Signal Transduction / drug effects
  • Toll-Like Receptor 2 / metabolism
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism


  • Chemokines
  • Chromatin
  • Histones
  • Nucleosomes
  • RNA, Small Interfering
  • TLR2 protein, human
  • TLR4 protein, human
  • Tlr4 protein, mouse
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Extracellular Signal-Regulated MAP Kinases