Novel chemokine-like activities of histones in tumor metastasis

Ruochan Chen, Yangchun Xie, Xiao Zhong, Yongmin Fu, Yan Huang, Yixiang Zhen, Pinhua Pan, Haichao Wang, David L. Bartlett, Timothy R. Billiar, Michael T. Lotze, Herbert J. Zeh, Xue Gong Fan*, Daolin Tang, Rui Kang

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


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.

Original languageEnglish
Pages (from-to)61728-61740
Number of pages13
Issue number38
StatePublished - 2016
Externally publishedYes


  • Hepatocellular carcinoma
  • Histone
  • Metastasis
  • NF-κB
  • TLR4


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