HDAC inhibitors stimulate LIFR when it is repressed by hypoxia or PTHrP in breast cancer

J Bone Oncol. 2021 Dec 1;31:100407. doi: 10.1016/j.jbo.2021.100407. eCollection 2021 Dec.

Abstract

Breast cancer cells frequently disseminate to the bone marrow, where they either induce osteolysis or enter a dormant state. Downregulation of leukemia inhibitory factor receptor (LIFR), a known breast tumor suppressor, enables otherwise dormant MCF7 human breast cancer cells to become aggressively osteolytic. Hypoxia (low oxygen tensions), which may develop in tumors as a pathological response to the metabolic demands of the proliferating cells and as a physiological state in the bone, downregulates LIFR in breast cancer cells independent of hypoxia-inducible factor (HIF) signaling. However, the mechanism by which LIFR is repressed in hypoxia is unknown. Histone deacetylase (HDAC) inhibitors stimulate LIFR by increasing histone acetylation in the proximal promoter and induce a dormancy phenotype in breast cancer cells inoculated into the mammary fat pad. We therefore aimed to determine whether hypoxia alters histone acetylation in the LIFR promoter, and whether HDAC inhibitors effectively stimulate LIFR in breast cancer cells residing in hypoxic microenvironments. Herein, we confirmed that disseminated MCF7 cells became hypoxic in the bone and that hypoxia increased the epigenetic transcriptional repressor H3K9me3 in the distal LIFR promoter while H3K9ac, which promotes transcription, was significantly reduced. Furthermore, HDAC inhibitor treatment rescued hypoxic repression and dramatically increased expression of LIFR, p38β, and p21, which regulate tumor dormancy. In a second model of LIFR repression, in which parathyroid hormone-related protein (PTHrP) suppresses LIFR expression, we found that PTHrP binds to the distal LIFR promoter, and that PTHrP suppression of LIFR protein is similarly reversed by HDAC inhibitor treatment. Together, these data suggest that HDAC inhibitors stimulate LIFR regardless of the way it is repressed by the microenvironment.