RGD Reference Report - Inhibition of histone demethylase JMJD1A improves anti-angiogenic therapy and reduces tumor-associated macrophages. - Rat Genome Database

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Inhibition of histone demethylase JMJD1A improves anti-angiogenic therapy and reduces tumor-associated macrophages.

Authors: Osawa, T  Tsuchida, R  Muramatsu, M  Shimamura, T  Wang, F  Suehiro, J  Kanki, Y  Wada, Y  Yuasa, Y  Aburatani, H  Miyano, S  Minami, T  Kodama, T  Shibuya, M 
Citation: Osawa T, etal., Cancer Res. 2013 May 15;73(10):3019-28. doi: 10.1158/0008-5472.CAN-12-3231. Epub 2013 Mar 14.
RGD ID: 9590219
Pubmed: PMID:23492365   (View Abstract at PubMed)
DOI: DOI:10.1158/0008-5472.CAN-12-3231   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cervical cancer severityIMP 9590219human gene in a mouse modelRGD 
cervical cancer severityISOKDM3A (Homo sapiens)9590219; 9590219human gene in a mouse modelRGD 

Objects Annotated

Genes (Rattus norvegicus)
Kdm3a  (lysine demethylase 3A)

Genes (Mus musculus)
Kdm3a  (lysine (K)-specific demethylase 3A)

Genes (Homo sapiens)
KDM3A  (lysine demethylase 3A)


Additional Information