Increased expression of histone demethylase JHDM1D under nutrient starvation suppresses tumor growth via down-regulating angiogenesis
Increased expression of histone demethylase JHDM1D under nutrient starvation suppresses tumor growth via down-regulating angiogenesis
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DOI：
10.1073/pnas.1108462109
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发表时间：
2011-12-20
影响因子：
11.1
通讯作者：
Shibuya, Masabumi
中科院分区：
文献类型：
--
作者：
Osawa, Tsuyoshi;Muramatsu, Masashi;Shibuya, Masabumi
组蛋白去甲基酶JHDM1D(也称为KDM7A)修饰组蛋白甲基化水平，并参与表观遗传基因调控；然而，JHDM1D在肿瘤进展中的作用尚不清楚。在这里，我们展示了JHDM1D通过调节血管生成而发挥肿瘤抑制作用。在体外长期营养饥饿的情况下，JHDM1D在小鼠和人癌细胞中的表达增加。在血管生成前切换处，无血管肿瘤组织中JHDM1D基因的表达增加，同时血管生成调节基因如VEGF-A的表达增加。在癌细胞中稳定表达JHDM1D或沉默JHDM1D的siRNA不影响细胞增殖、非贴壁细胞生长或细胞周期进展。值得注意的是，表达JHDM1D的小鼠黑色素瘤(B16)和人宫颈癌(HeLa)细胞在体内的肿瘤生长速度明显慢于原始细胞。肿瘤生长的减少与CD31(+)血管形成减少和CD11b(+)巨噬细胞向肿瘤组织的渗透减少有关。在表达JHDM1D的B16和HeLa细胞的移植瘤中，多种血管生成因子如血管内皮生长因子B和血管生成素的表达减少。我们的结果提供了证据，证明在营养饥饿下，JHDM1D表达增加通过下调血管生成来抑制肿瘤生长。
Histone demethylase JHDM1D (also known as KDM7A) modifies the level of methylation in histone and participates in epigenetic gene regulation; however, the role of JHDM1D in tumor progression is unknown. Here, we show that JHDM1D plays a tumor-suppressive role by regulating angiogenesis. Expression of JHDM1D was increased in mouse and human cancer cells under long-term nutrient starvation in vitro. Expression of JHDM1D mRNA was increased within avascular tumor tissue at the preangiogenic switch, along with increased expression of angiogenesis-regulating genes such as Vegf-A. Stable expression of JHDM1D cDNA or siRNA silencing of JHDM1D in cancer cells did not affect cell proliferation, anchorage-independent cell growth, or cell cycle progression in vitro. Notably, JHDM1D-expressing mouse melanoma (B16) and human cervical carcinoma (HeLa) cells exhibited significantly slower tumor growth in vivo compared with the original cells. This reduction in tumor growth was associated with decreased formation of CD31(+) blood vessels and reduced infiltration of CD11b(+) macrophage linage cells into tumor tissues. Expression of multiple angiogenic factors such as VEGF-B and angiopoietins was decreased in tumor xenografts of JHDM1D-expressing B16 and HeLa cells. Our results provide evidence that increased JHDM1D expression suppressed tumor growth by down-regulating angiogenesis under nutrient starvation.