Herein, we demonstrated that NKX2-8 transcriptionally downregulated the PTHrP expression through directly interacting with histone deacetylase 1 (HDAC1) on the PTHrP promoter, resulting in a reduction of histone H3K27 acetylation, which transcriptionally downregulated PTHrP level in breast cancer. Here, PTHLH is linked to breast cancer.