Inhibition of Histone Demethylase JMJD1A Improves Anti-Angiogenic Therapy and Reduces Tumor-Associated Macrophages

Abstract

Antiangiogenic strategies can be effective for cancer therapy, but like all therapies resistance poses a major clinical challenge. Hypoxia and nutrient starvation select for aggressive qualities that may render tumors resistant to antiangiogenic attack. Here, we show that hypoxia and nutrient starvation cooperate to drive tumor aggressiveness through epigenetic regulation of the histone demethylase JMJD1A (JHDM2A; KDM3A). In cancer cells rendered resistant to long-term hypoxia and nutrient starvation, we documented a stimulation of AKT phosphorylation, cell morphologic changes, cell migration, invasion, and anchorage-independent growth in culture. These qualities associated in vivo with increased angiogenesis and infiltration of macrophages into tumor tissues. Through expression microarray analysis, we identified a cluster of functional drivers such as VEGFA, FGF18, and JMJD1A, the latter which was upregulated in vitro under conditions of hypoxia and nutrient starvation and in vivo before activation of the angiogenic switch or the prerefractory phase of antiangiogenic therapy. JMJD1A inhibition suppressed tumor growth by downregulating angiogenesis and macrophage infiltration, by suppressing expression of FGF2, HGF, and ANG2. Notably, JMJD1A inhibition enhanced the antitumor effects of the anti-VEGF compound bevacizumab and the VEGFR/KDR inhibitor sunitinib. Our results form the foundation of a strategy to attack hypoxia-and nutrient starvation-resistant cancer cells as an approach to leverage antiangiogenic treatments and limit resistance to them. Cancer Res; 73(10); 3019-28. Ó2013 AACR.

Nitric Oxide Modifies Global Histone Methylation by Inhibiting Jumonji C Domain-containing Demethylases

“…In one particular study, immunohistochemical analysis revealed higher levels of KDM3A near the vessels of renal cell carcinomas, implicating a possible role in regulation of VEGF (65). Furthermore, inhibition of KDM3A improved outcomes of the anti-angiogenic VEGF antibody, bevacizumab (66). Thus, paradoxically, a combination of VEGF inhibitors and ⅐ NO might prove beneficial despite the fact that ⅐ NO drives up-regulation of angiogenesis through VEGF (67).…”

Hypoxia-inducible KDM3A addiction in multiple myeloma

“…For example, Osawa et al 19 reported that KDM3A is induced by hypoxia or by starvation, leading to the production of angiogenic factors by tumor cells and promotion of macrophage infiltration into tumors. It has also been reported that in solid tumors (such as breast cancer and rectal cancer), high KDM3A expression is associated with a poor prognosis.…”

“…[18][19][20] We performed a western blot analysis of KDM3A and KDM7A expression in normoxia-and hypoxia-subjected myeloma cell lines and found that expression of KDM3A was more strongly increased than that of KDM7A under hypoxia (Figure 2A-B). The increase in KDM3A expression was time-dependent, but that of KDM7A was not ( Figure 2B).…”

Novel insight into MALAT-1 in cancer: Therapeutic targets and clinical applications

“…In addtion, JMJD1A increased MALAT1 gene transcription by demethylating histone H3K9. Addtional studies revealed that JMJD1A increased MALAT-1 expression by directly binding to the MALAT-1 gene promoter, which lead to histone H3K9 demethylation by activating JMJD1A gene transcription (59,60). Overall, the findings suggest that the development of more potent JMJD1A/MALAT-1 inhibitors may be used for the prevention of tumor metastasis (37).…”