Hypoxia and Hormone-Mediated Pathways Converge at the Histone Demethylase KDM4B in Cancer

Abstract

Hormones play an important role in pathophysiology. The hormone receptors, such as estrogen receptor alpha and androgen receptor in breast cancer and prostate cancer, are critical to cancer cell proliferation and tumor growth. In this review we focused on the cross-talk between hormone and hypoxia pathways, particularly in breast cancer. We delineated a novel signaling pathway from estrogen receptor to hypoxia-inducible factor 1, and discussed the role of this pathway in endocrine therapy resistance. Further, we discussed the estrogen and hypoxia pathways converging at histone demethylase KDM4B, an important epigenetic modifier in cancer.

Keywords: KDM4B; endocrine therapy resistance; estrogen receptor alpha; hypoxia-inducible factor 1.

Figure 1

Estrogen pathway directly drives HIF-1α expression. (A) HIF-1α gene bears a canonical estrogen receptor binding element (ERE), with a FOXA1 binding site downstream of ERE; (B) When ERα is bound by its ligand it drives the expression of HIF-1α. However, ERα antagonists block the expression of HIF-1α; (C) The pathways mediated by hypoxia, estrogen, metabolites, and cancer genes converge on HIF-1α, which drives a plethora of genes that are involved in multiple biological processes, cancer progression, and therapeutic resistance.

Figure 2

Hypoxia and estrogen pathways converge at KDM4B for cancer cell proliferation in ERα positive breast cancer. (A) KDM4B is one of the genes responsive to both estrogen and hypoxia-mediated pathways; (B) Regardless of endocrine therapy resistance, ERα drives KDM4B expression, which is required for G2/M phase progression.