Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Biochem J. 2012 Sep 15;446(3):415-25. doi: 10.1042/BJ20112050.
Increased de novo lipogenesis is a hallmark of aggressive cancers. Lipid droplets, the major form of cytosolic lipid storage, have been implicated in cancer cell proliferation and tumorigenesis. Recently, we identified the ERLIN2 [ER (endoplasmic reticulum) lipid raft-associated 2) gene that is amplified and overexpressed in aggressive human breast cancer. Previous studies demonstrated that ERLIN2 plays a supporting oncogenic role by facilitating the transformation of human breast cancer cells. In the present study, we found that ERLIN2 supports cancer cell growth by regulating cytosolic lipid droplet production. ERLIN2 is preferably expressed in human breast cancer cells or hepatoma cells and is inducible by insulin signalling or when cells are cultured in lipoprotein-deficient medium. Increased expression of ERLIN2 promotes the accumulation of cytosolic lipid droplets in breast cancer cells or hepatoma cells in response to insulin or overload of unsaturated fatty acids. ERLIN2 regulates activation of SREBP (sterol regulatory element-binding protein) 1c, the key regulator of de novo lipogenesis, in cancer cells. ERLIN2 was found to bind to INSIG1 (insulin-induced gene 1), a key ER membrane protein that blocks SREBP activation. Consistent with the role of ERLIN2 in regulating cytosolic lipid content, down-regulation of ERLIN2 in breast cancer or hepatoma cells led to lower cell proliferation rates. The present study revealed a novel role for ERLIN2 in supporting cancer cell growth by promoting the activation of the key lipogenic regulator SREBP1c and the production of cytosolic lipid droplets. The identification of ERLIN2 as a regulator of cytosolic lipid content in cancer cells has important implications for understanding the molecular basis of tumorigenesis and the treatment of cancer.
从头合成的脂肪生成增加是侵袭性癌症的一个标志。脂滴是细胞溶质脂质储存的主要形式，已被牵连到癌细胞增殖和肿瘤发生中。最近，我们鉴定了 ERLIN2 [内质网（ER）脂筏相关 2 基因]，该基因在侵袭性人乳腺癌中扩增和过表达。先前的研究表明，ERLIN2 通过促进人乳腺癌细胞的转化发挥支持致癌的作用。在本研究中，我们发现 ERLIN2 通过调节细胞溶质脂滴的产生来支持癌细胞的生长。ERLIN2 优选在人乳腺癌细胞或肝癌细胞中表达，并可被胰岛素信号或细胞在脂蛋白缺乏的培养基中培养诱导。ERLIN2 表达增加可促进乳腺癌细胞或肝癌细胞中细胞溶质脂滴的积累，以响应胰岛素或不饱和脂肪酸的超负荷。ERLIN2 调节固醇调节元件结合蛋白 1c（SREBP1c）的激活，SREBP1c 是从头脂肪生成的关键调节剂。发现 ERLIN2 与 INSIG1（胰岛素诱导基因 1）结合，INSIG1 是一种阻止 SREBP 激活的关键 ER 膜蛋白。与 ERLIN2 在调节细胞溶质脂质含量中的作用一致，乳腺癌或肝癌细胞中 ERLIN2 的下调导致细胞增殖率降低。本研究揭示了 ERLIN2 通过促进关键脂生成调节剂 SREBP1c 的激活和细胞溶质脂滴的产生来支持癌细胞生长的新作用。鉴定 ERLIN2 作为癌细胞中细胞溶质脂质含量的调节剂，对于理解肿瘤发生的分子基础和癌症的治疗具有重要意义。
