Lu Fangjin, Zheng Ying, Donkor Paul Owusu, Zou Peng, Mu Ping
Tianjin State Key Laboratory of Modern Chinese Medicine, School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
Oncol Res. 2016;24(3):171-9. doi: 10.3727/096504016X14634208142987.
The cyclic-AMP response element-binding protein (CREB), a well-known nuclear transcription factor, has been shown to play an essential role in many cellular processes, including differentiation, cell survival, and cell proliferation, by regulating the expression of downstream genes. Recently, increased expression of CREB was frequently found in various tumors, indicating that CREB is implicated in the process of tumorigenesis. However, the effects of CREB on Hodgkin lymphoma (HL) remain unknown. To clarify the role of CREB in HL, we performed knockdown experiments in HL. We found that downregulation of CREB by short hairpin RNA (shRNA) resulted in enhancement of cell proliferation and promotion of G1/S phase transition, and these effects can be rescued by expression of shRNA-resistant CREB. Meanwhile, the expression level of cell cycle-related proteins, such as cyclin D1, cyclin E1, cyclin-dependent kinase 2 (CDK2), and CDK4, was elevated in response to depletion of CREB. Furthermore, we performed chromatin immunoprecipitation (ChIP) assay and confirmed that CREB directly bound to the promoter regions of these genes, which consequently contributed to the regulation of cell cycle. Consistent with our results, a clinical database showed that high expression of CREB correlates with favorable prognosis in B-cell lymphoma patients, which is totally different from the function of CREB in other cancers such as colorectal cancer, acute myeloid leukemia, and some endocrine cancers. Taken together, all of these features of CREB in HL strongly support its role as a tumor suppressor gene that can decelerate cell proliferation by inhibiting the expression of several cell cycle-related genes. Our results provide new evidence for prognosis prediction of HL and a promising therapeutic strategy for HL patients.
环磷腺苷反应元件结合蛋白（CREB）是一种著名的核转录因子，已被证明通过调节下游基因的表达在许多细胞过程中发挥重要作用，包括分化、细胞存活和细胞增殖。最近，在各种肿瘤中经常发现CREB表达增加，这表明CREB与肿瘤发生过程有关。然而，CREB对霍奇金淋巴瘤（HL）的影响仍不清楚。为了阐明CREB在HL中的作用，我们在HL中进行了敲低实验。我们发现，短发夹RNA（shRNA）下调CREB导致细胞增殖增强和G1/S期转换促进，并且这些作用可以通过表达抗shRNA的CREB来挽救。同时，细胞周期相关蛋白如细胞周期蛋白D1、细胞周期蛋白E1、细胞周期蛋白依赖性激酶2（CDK2）和CDK4的表达水平在CREB缺失时升高。此外，我们进行了染色质免疫沉淀（ChIP）分析，并证实CREB直接结合这些基因的启动子区域，从而有助于细胞周期的调节。与我们的结果一致，一个临床数据库显示，CREB的高表达与B细胞淋巴瘤患者的良好预后相关，这与CREB在其他癌症如结直肠癌、急性髓性白血病和一些内分泌癌中的功能完全不同。综上所述，CREB在HL中的所有这些特征有力地支持了它作为一种肿瘤抑制基因的作用，即通过抑制几种细胞周期相关基因的表达来减缓细胞增殖。我们的结果为HL的预后预测提供了新的证据，并为HL患者提供了一种有前景的治疗策略。
