The lysine specific demethylase-1 (LSD1/KDM1A) regulates VEGF-A expression in prostate cancer.
The lysine specific demethylase-1 (LSD1/KDM1A) regulates VEGF-A expression in prostate cancer.
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DOI：
10.1016/j.molonc.2013.01.003
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发表时间：
2013-06
影响因子：
6.6
通讯作者：
Mongan, Nigel P.
中科院分区：
文献类型：
--
作者：
Kashyap, Vasundhra;Ahmad, Shafqat;Nilsson, Emeli M.;Helczynski, Leszek;Kenna, Sinead;Persson, Jenny Liao;Gudas, Lorraine J.;Mongan, Nigel P.
复发性前列腺癌仍然是一个主要的临床挑战。赖氨酸特异性脱甲基酶-1（LSD 1/KDM 1A）与含有JmjC结构域的JMJD2A和JMJD2C蛋白一起，已成为组蛋白赖氨酸甲基化的关键调节剂。LSD1-JMJD2复合物在特定基因启动子处作为激素激活的雄激素和雌激素受体的转录共调节因子发挥作用。LSD 1还调节DNA甲基化和p53功能。LSD1在许多癌症中过表达，包括前列腺癌，其机制未知。我们研究了LSD 1和JMJD 2A在恶性前列腺标本中的表达。我们将LSD 1和JMJD 2A的表达与前列腺癌进展的已知介质：VEGF-A和细胞周期蛋白A1相关联。我们发现LSD1的表达升高，而不是JMJD2A，与前列腺癌复发和VEGF-A表达增加相关。我们表明，在前列腺癌细胞中使用siRNA功能性耗竭LSD 1表达降低VEGF-A并阻断雄激素诱导的VEGF-A、PSA和Tmprss 2表达。我们证明，LSD 1的药理学抑制降低了雄激素依赖性（LnCaP）和非依赖性细胞系（LnCaP：C42，PC3）的增殖。我们发现LSD 1过表达和促血管生成途径活性增加之间存在直接的机制联系。靶向LSD 1活性的新疗法应该可用于治疗激素依赖性和非依赖性前列腺癌。
Recurrent prostate cancer remains a major clinical challenge. The lysine specific demethylase-1 (LSD1/KDM1A), together with the JmjC domain-containing JMJD2A and JMJD2C proteins, have emerged as critical regulators of histone lysine methylation. The LSD1-JMJD2 complex functions as a transcriptional co-regulator of hormone activated androgen and estrogen receptors at specific gene promoters. LSD1 also regulates DNA methylation and p53 function. LSD1 is overexpressed in numerous cancers including prostate cancer through an unknown mechanism. We investigated expression of the LSD1 and JMJD2A in malignant human prostate specimens. We correlated LSD1 and JMJD2A expression with known mediators of prostate cancer progression: VEGF-A and cyclin A1. We show that elevated expression of LSD1, but not JMJD2A, correlates with prostate cancer recurrence and with increased VEGF-A expression. We show that functional depletion of LSD1 expression using siRNA in prostate cancer cells decreases VEGF-A and blocks androgen induced VEGF-A, PSA and Tmprss2 expression. We demonstrate that pharmacological inhibition of LSD1 reduces proliferation of both androgen dependent (LnCaP) and independent cell lines (LnCaP:C42, PC3). We show a direct mechanistic link between LSD1 over-expression and increased activity of pro-angiogenic pathways. New therapies targeting LSD1 activity should be useful in the treatment of hormone dependent and independent prostate cancer.
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影响因子：
9.8
作者：
ENCODE Project Consortium
通讯作者：
ENCODE Project Consortium
影响因子：
6.2
作者：
Picus, Joel;Halabi, Susan;Small, Eric J.
通讯作者：
Small, Eric J.
影响因子：
2.1
作者：
Ferrer, FA;Miller, LJ;Kreutzer, DL
通讯作者：
Kreutzer, DL
影响因子：
50.3
作者：
Cai C;He HH;Chen S;Coleman I;Wang H;Fang Z;Chen S;Nelson PS;Liu XS;Brown M;Balk SP
通讯作者：
Balk SP
影响因子：
64.8
作者：
Berger, Michael F.;Lawrence, Michael S.;Demichelis, Francesca;Drier, Yotam;Cibulskis, Kristian;Sivachenko, Andrey Y.;Sboner, Andrea;Esgueva, Raquel;Pflueger, Dorothee;Sougnez, Carrie;Onofrio, Robert;Carter, Scott L.;Park, Kyung;Habegger, Lukas;Ambrogio, Lauren;Fennell, Timothy;Parkin, Melissa;Saksena, Gordon;Voet, Douglas;Ramos, Alex H.;Pugh, Trevor J.;Wilkinson, Jane;Fisher, Sheila;Winckler, Wendy;Mahan, Scott;Ardlie, Kristin;Baldwin, Jennifer;Simons, Jonathan W.;Kitabayashi, Naoki;MacDonald, Theresa Y.;Kantoff, Philip W.;Chin, Lynda;Gabriel, Stacey B.;Gerstein, Mark B.;Golub, Todd R.;Meyerson, Matthew;Tewari, Ashutosh;Lander, Eric S.;Getz, Gad;Rubin, Mark A.;Garraway, Levi A.
通讯作者：
Garraway, Levi A.