組蛋白乙酰基化是常見的表觀遺傳修飾,?；騿幼訁^(qū)域的高水平組蛋白乙酰基化往往會促進該基因的表達,。異常的組蛋白乙?；c各種病理過程緊密相關。HDAC是重要的組蛋白乙?；{(diào)控因子,，它們在很多癌癥組織中的表達過高。它們的抑制劑能有效地誘導不同組織來源的癌細胞凋亡,，但在同樣的濃度下,，對正常細胞的毒性作用很小，因此是一類潛在的具有良好應用前景的新型抗腫瘤化合物,。胚胎性癌細胞（embryonic carcinoma cells）是惡性畸胎瘤組織中分化程度低,、惡性程度高的那一部分細胞。它們在畸胎瘤復發(fā)和轉移過程中扮演著重要角色,。傳統(tǒng)化療藥物對于這類癌細胞的治療效果并不理想,。已有研究表明，HDAC抑制劑能夠有效地誘導胚胎性癌細胞凋亡,，但是目前并不清楚其中的分子機制,。
上海生科院生化與細胞所宋建國研究組博士研究生舒廣文等人的研究工作表明，Zac1基因的表達上調(diào)在組蛋白去乙?；福╤istone deacetylase,，HDAC）抑制劑誘導的胚胎性癌細胞凋亡過程中起著關鍵作用。
研究揭示,，Zac1是NF-kB的抑制因子,。HDAC抑制劑通過上調(diào)其啟動子區(qū)域的組蛋白乙酰化水平而誘導它的表達,。Zac1蛋白分子通過與NF-kB的p65亞基C-末端的直接結合而抑制其第468和536位絲氨酸殘基的磷酸化，引起細胞內(nèi)抗凋亡信號通路NF-kB活性的抑制,。這一事件的結果是胚胎性癌細胞內(nèi)原有的抑凋亡-促凋亡信號通路的平衡朝著促凋亡信號占優(yōu)勢這一方向傾斜,，從而導致細胞凋亡,。該研究為HDAC抑制劑誘導胚胎性癌細胞凋亡的分子機制提供了重大的新穎認識，對于開發(fā)腫瘤治療的分子靶點具有潛在的臨床醫(yī)學價值,。該研究工作是在與王琛研究員的合作下完成的,。
該研究工作得到國家基金委經(jīng)費的資助，于5月6日在國際著名學術雜志Cell Death & Differentiation 上在線發(fā)表,。（生物谷Bioon.com）
生物谷推薦原文出處：
Cell Death & Differentiation DOI： doi:10.1038/cdd.2011.51
Zac1 is a histone acetylation-regulated NF-|[kappa]|B suppressor that mediates histone deacetylase inhibitor-induced apoptosis
G Shu, Y Tang, Y Zhou, C Wang, J-G Song
Histone deacetylase (HDAC) inhibitors are a class of promising anticancer reagents. They are able to induce apoptosis in embryonic carcinoma (EC) cells. However, the underlying mechanism remains poorly understood. Here we show that increased expression of zinc-finger protein regulator of apoptosis and cell-cycle arrest (Zac1) is implicated in HDAC inhibitor-induced apoptosis in F9 and P19 EC cells. By chromatin immunoprecipitation analysis we identified that increased Zac1 expression is mediated by histone acetylation of the Zac1 promoter region. Knockdown of Zac1 inhibited HDAC inhibitor-induced cell apoptosis. Moreover, HDAC inhibitors repressed nuclear factor-κB (NF-κB) activity, and this effect is abrogated by Zac1 knockdown. Consistently, Zac1 overexpression suppressed cellular NF-κB activity. Further investigation showed that Zac1 inhibits NF-κB activity by interacting with the C-terminus of the p65 subunit, which suppresses the phosphorylation of p65 at Ser468 and Ser536 residues. These results indicate that Zac1 is a histone acetylation-regulated suppressor of NF-κB, which is induced and implicated in HDAC inhibitor-mediated EC cell apoptosis.
