High mobility group box 1 (
HMGB1) is a 25-kDa
chromatin-associated
protein that
aids in transcription and DNA repair by directly binding to
DNA and altering its conformation. Additionally,
HMGB1 can act as an extracellular
ligand. When released from dying or stressed cells,
HMGB1 binds to the RAGE receptor and activates the p42/44 MAP
kinase (MAPK) cascade.
HMGB1 is overexpressed in many types of
cancer and frequently associated with
tumor stage and
metastasis. This has predominantly been attributed to an autocrine function that drives MAPK pathway activity. However, by using
tumor cells with activating MAPK pathway mutations, we have identified a role for
HMGB1 in promoting
metastasis and
tumor growth that is independent of this pathway. In the absence of
HMGB1, these
tumor cells show defective in vitro migration as well as reduced
metastasis and
tumor growth in vivo despite high p42/44 phosphorylation. We found that
semaphorin 3A (
SEMA3A), previously shown to act as a suppressor of angiogenesis and migration, was highly increased during expression in the absence of
HMGB1.
SEMA3A/
HMGB1 double knockdown rescued the migration defect in
HMGB1 single knockdown cells.
HMGB1 bound at the
semaphorin 3A genomic locus, promoted hetrochromatin formation, and decreased occupancy of acetylated
histones. Based on human
tumor gene expression databases,
HMGB1 was significantly inversely correlated with
SEMA3A, suggesting that this mechanism may be more widely relevant in different
cancer types.