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

Novel chemokine-like activities of histones in tumor metastasis.

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Department of Infectious Diseases and State Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Department of Pneumology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
Laboratory of Emergency Medicine, The Feinstein Institute for Medical Research, Manhasset, New York 11030, USA.
Center for DAMP Biology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510150, China.


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.


NF-κB; TLR4; hepatocellular carcinoma; histone; metastasis

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