Restoration of transforming growth factor-β signaling through receptor RI induction by histone deacetylase activity inhibition in breast cancer cells
Restoration of transforming growth factor-β signaling through receptor RI induction by histone deacetylase activity inhibition in breast cancer cells
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DOI：
10.1074/jbc.m402691200
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发表时间：
2004-07-30
影响因子：
4.8
通讯作者：
Brattain, MG
中科院分区：
文献类型：
--
作者：
Ammanamanchi, S;Brattain, MG
众所周知，I 型 (RI) 和 II 型 (RII) TGF-β 受体失调导致转化生长因子-β (TGF-β) 反应丧失，从而导致肿瘤发生。由于 TGF-β 受体的表达减少，表达雌激素受体的乳腺癌细胞难以受到 TGF-β 介导的生长控制。尽管 TGF-β 与 RI 的结合需要 RII，但 RI 负责通过 Smad 蛋白家族直接转导 TGF-β 信号。用组蛋白脱乙酰酶 (HDAC) 抑制剂辛二酰苯胺异羟肟酸 (SAHA) 处理表达雌激素受体的 MCF-7L 和 ZR75 乳腺癌细胞，可显着诱导 RI。在 SAHA 处理的细胞中观察到乙酰化组蛋白 H3 和 H4 的积累。染色质免疫沉淀分析，随后使用 RI 启动子特异性引物进行 PCR，表明与 RI 基因相关的染色质中乙酰化组蛋白的积累，表明组蛋白脱乙酰化参与 RI 的转录失活。 SAHA 治疗通过抑制 Sp1/Sp3 相关的 HDAC 活性来刺激 RI 启动子活性。组蛋白乙酰转移酶 p300 刺激 RI 启动子活性，从而进一步证实 HDAC 活性参与 RI 的转录抑制。值得注意的是，SAHA 介导的 RI 再生恢复了乳腺癌细胞中的 TGF-β 反应。
The loss of transforming growth factor-beta (TGF-beta) response due to the dysregulation of TGF-beta receptors type I (RI) and type II (RII) is well known for its contribution to oncogenesis. Estrogen receptor-expressing breast cancer cells are refractory to TGF-beta-mediated growth control because of the reduced expression of TGF-beta receptors. Although RII is required for the binding of TGF-beta to RI, RI is responsible for directly transducing TGF-beta signals through the Smad protein family. Treatment of estrogen receptor-expressing MCF-7L and ZR75 breast cancer cells with the histone deacetylase ( HDAC) inhibitor suberoylanilide hydroxamic acid ( SAHA) led to a dramatic induction of RI. Accumulation of acetylated histones H3 and H4 was observed in the SAHA-treated cells. Chromatin immunoprecipitation analysis followed by PCR with RI promoter-specific primers indicated an accumulation of acetylated histones in chromatin associated with the RI gene, suggesting that histone deacetylation was involved in the transcriptional inactivation of RI. SAHA treatment stimulated RI promoter activity through the inhibition of Sp1/Sp3-associated HDAC activity. Histone acetyltransferase p300 stimulated RI promoter activity, thus further confirming the involvement of HDAC activity in the transcriptional repression of RI. Significantly, SAHA-mediated RI regeneration restored the TGF-beta response in breast cancer cells.