Gatla Himavanth R, Zou Yue, Uddin Mohammad M, Vancurova Ivana
Department of Biological Sciences, St. John's University, New York City, NY 11439, USA.
Oncotarget. 2017 Aug 7;8(41):70798-70810. doi: 10.18632/oncotarget.19990. eCollection 2017 Sep 19.
Although inhibitors of epigenetic regulators have been effective in the treatment of cutaneous T cell lymphoma (CTCL) and other hematopoietic malignancies, they have been less effective in solid tumors, including ovarian cancer (OC). We have previously shown that inhibition of histone deacetylase (HDAC) activity induces expression of the pro-inflammatory and pro-angiogenic chemokine interleukin-8 (CXCL8, IL-8) in OC cells, resulting in their increased survival and proliferation. Here, we show that in addition to ovarian cancer SKOV3, OVCAR3, and CAOV3 cells, HDAC inhibition induces the CXCL8 expression in HeLa cells, but not in CTCL Hut-78 cells. In OC cells, the CXCL8 expression is induced by pharmacological inhibition of class I HDACs. Interestingly, while an individual suppression of HDAC1, HDAC2, or HDAC3 by corresponding siRNAs inhibits the CXCL8 expression, their simultaneous suppression induces the CXCL8 expression. The induced CXCL8 expression in OC cells is dependent on histone acetyltransferase (HAT) activity of CREB-binding protein (CBP), but not p300, and is associated with HAT-dependent p65 recruitment to CXCL8 promoter. Together, our results show that the CXCL8 expression in OC cells is induced by combined inhibition of HDAC1, -2, and -3, and silenced by suppression of HAT activity of CBP. In addition, our data indicate that the induced CXCL8 expression may be responsible for the limited effectiveness of HDAC inhibitors in OC and perhaps other solid cancers characterized by CXCL8 overexpression, and suggest that targeting class I HDACs and CBP may provide novel combination strategies by limiting the induced CXCL8 expression.
尽管表观遗传调节剂抑制剂在皮肤T细胞淋巴瘤（CTCL）和其他血液系统恶性肿瘤的治疗中有效，但它们在包括卵巢癌（OC）在内的实体瘤中效果较差。我们之前已经表明，抑制组蛋白脱乙酰酶（HDAC）活性会诱导OC细胞中促炎和促血管生成趋化因子白细胞介素-8（CXCL8，IL-8）的表达，从而导致其存活率和增殖增加。在此，我们表明，除了卵巢癌SKOV3、OVCAR3和CAOV3细胞外，HDAC抑制还会诱导HeLa细胞中CXCL8的表达，但不会诱导CTCL Hut-78细胞中CXCL8的表达。在OC细胞中，I类HDAC的药理学抑制会诱导CXCL8的表达。有趣的是，虽然相应的小干扰RNA（siRNA）单独抑制HDAC1、HDAC2或HDAC3会抑制CXCL8的表达，但它们同时被抑制时却会诱导CXCL8的表达。OC细胞中诱导的CXCL8表达依赖于CREB结合蛋白（CBP）的组蛋白乙酰转移酶（HAT）活性，而不依赖于p300，并且与HAT依赖的p65募集到CXCL8启动子有关。总之，我们的结果表明，OC细胞中CXCL8的表达是由HDAC1、-2和-3的联合抑制诱导的，并通过抑制CBP的HAT活性而沉默。此外，我们的数据表明，诱导的CXCL8表达可能是HDAC抑制剂在OC以及可能其他以CXCL8过表达为特征的实体癌中疗效有限的原因，并表明靶向I类HDAC和CBP可能通过限制诱导的CXCL8表达提供新的联合治疗策略。
