Boukhari Abdelaziz, Alhosin Mahmoud, Bronner Christian, Sagini Krizia, Truchot Cécile, Sick Emilie, Schini-Kerth Valerie B, André Philippe, Mély Yves, Mousli Marc, Gies Jean-Pierre
CNRS UMR 7213 Laboratoire de Biophotonique et Pharmacologie, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, Parc d'innovation, Illkirch Cedex, France.
Anticancer Res. 2015 Jan;35(1):149-57.
CD47, an integrin-associated protein is over-expressed in several tumors including glioblastomas. Activation of CD47 induces proliferation of human astrocytoma cells but not normal astrocytes via an Akt-dependent way. However, the pathways mediating this process are still unknown. The epigenetic integrator UHRF1 (Ubiquitin-like containing PHD and RING Finger 1) is over-expressed in various cancers and plays a vital role in the silencing of numerous tumor suppressor genes including p16(INK4A), thereby promoting cell proliferation. The aim of the present study was to investigate the role of UHRF1 and p16(INK4A) in CD47-induced effects. Herein we showed that activation of CD47 in human astrocytoma cell lines U87 and CCF- STTG1 (Grade IV), up-regulated the expression of UHRF1 with subsequent down-regulation of p16(INK4A), thus promoting cell proliferation. Blockage of CD47 using a blocking antibody down-regulated UHRF1 expression, accompanied by a re-expression of p16(INK4A), conducting to decreased cell proliferation in both cancer cell lines. Neither CD47 activation nor its blocking has any effect on UHRF1/p16(INK4A) expression in normal human astrocytes. Depletion of CD47 in the U87 cell line resulted in down-regulation of UHRF1. We also found that CD47 activated the inflammatory genes IL-6, IL-7 and MCP-1 by a NF-κB-dependent mechanism in human astrocytoma but not in normal astrocytes. In conclusion, the present findings indicate that CD47 activation increases expression of UHRF1 and suggest, for the first time, that CD47 regulates the epigenetic code by targeting UHRF1. This could represent a new pathway towards cell proliferation and metastasis.
整合素相关蛋白CD47在包括胶质母细胞瘤在内的多种肿瘤中过度表达。CD47的激活通过Akt依赖的方式诱导人星形细胞瘤细胞而非正常星形胶质细胞的增殖。然而，介导这一过程的途径仍不清楚。表观遗传整合因子UHRF1（含PHD和RING结构域的泛素样蛋白1）在多种癌症中过度表达，并在包括p16(INK4A)在内的众多肿瘤抑制基因的沉默中发挥重要作用，从而促进细胞增殖。本研究的目的是探讨UHRF1和p16(INK4A)在CD47诱导效应中的作用。在此我们表明，在人星形细胞瘤细胞系U87和CCF-STTG1（IV级）中激活CD47，上调了UHRF1的表达，随后p16(INK4A)表达下调，从而促进细胞增殖。使用阻断抗体阻断CD47可下调UHRF1表达，同时p16(INK4A)重新表达，导致两种癌细胞系中的细胞增殖减少。CD47的激活或阻断对正常人星形胶质细胞中UHRF1/p16(INK4A)的表达均无影响。U87细胞系中CD47的缺失导致UHRF1下调。我们还发现，CD47通过NF-κB依赖的机制激活人星形细胞瘤中的炎症基因IL-6、IL-7和MCP-1，但在正常星形胶质细胞中不激活。总之，本研究结果表明CD47激活增加了UHRF1的表达，并首次表明CD47通过靶向UHRF1调节表观遗传密码。这可能代表了一条通向细胞增殖和转移的新途径。
