Aberrant B7-H4 expression in
cancer tissues serves as a novel prognostic
biomarker for poor survival in patients with
cancer. However, the factor(s) that induce
cancer cell-associated B7-H4 remain to be fully elucidated. We herein demonstrate that
hypoxia upregulates B7-H4 transcription in primary CD138(+)
multiple myeloma cells and
cancer cell lines. In support of this finding, analysis of the
Multiple Myeloma Genomics Portal (
MMGP) data set revealed a positive correlation between the
mRNA expression levels of B7-H4 and the endogenous
hypoxia marker carbonic anhydrogenase 9.
Hypoxia-induced B7-H4 expression was detected in the cytoplasm, but not in
cancer cell membranes.
Chromatin immunoprecipitation analysis demonstrated binding of
hypoxia-inducible factor-1α (HIF-1α) to proximal
hypoxia-response element (HRE) sites within the B7-H4 promoter. Knockdown of HIF-1α and pharmacological inhibition of HIF-1α diminished B7-H4 expression. Furthermore, knockdown of cytoplasmic B7-H4 in MCF-7 decreased the S-phase cell population under
hypoxia. Finally,
MMGP analysis revealed a positive correlation between the transcript levels of B7-H4 and proliferation-related genes including MKI67, CCNA1, and Myc in several patients with
multiple myeloma. Our results provide insight into the mechanisms underlying B7-H4 upregulation and its role in
cancer cell proliferation in a hypoxic tumor microenvironment.