Aldaalis Arwa, Bengoechea-Alonso Maria T, Ericsson Johan
Division of Biological and Biomedical Sciences, College of Health and Life Sciences, Hamad Bin Khalifa University, Education City, Doha, Qatar.
School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
Front Oncol. 2022 Aug 24;12:942386. doi: 10.3389/fonc.2022.942386. eCollection 2022.
The sterol regulatory-element binding protein (SREBP) family of transcription factors regulates cholesterol, fatty acid, and triglyceride synthesis and metabolism. However, they are also targeted by the ubiquitin ligase Fbw7, a major tumor suppressor, suggesting that they could regulate cell growth. Indeed, enhanced lipid synthesis is a hallmark of many human tumors. Thus, the SREBP pathway has recently emerged as a potential target for cancer therapy. We have previously demonstrated that one of these transcription factors, SREBP1, is stabilized and remains associated with target promoters during mitosis, suggesting that the expression of these target genes could be important as cells enter G1 and transcription is restored. Activation of cyclin D-cdk4/6 complexes is critical for the phosphorylation and inactivation of the retinoblastoma protein (Rb) family of transcriptional repressors and progression through the G1 phase of the cell cycle. Importantly, the cyclin D-cdk4/6-Rb regulatory axis is frequently dysregulated in human cancer. In the current manuscript, we demonstrate that SREBP1 activates the expression of cyclin D1, a coactivator of cdk4 and cdk6, by binding to an E-box in the cyclin D1 promoter. Consequently, inactivation of SREBP1 in human liver and breast cancer cell lines reduces the expression of cyclin D1 and attenuates Rb phosphorylation. Rb phosphorylation in these cells can be rescued by restoring cyclin D1 expression. On the other hand, expression of active SREBP1 induced the expression of cyclin D1 and increased the phosphorylation of Rb in a manner dependent on cyclin D1 and cdk4/6 activity. Inactivation of SREBP1 resulted in reduced expression of cyclin D1, attenuated phosphorylation of Rb, and reduced proliferation. Inactivation of SREBP1 also reduced the insulin-dependent regulation of the cyclin D1 gene. At the same time, SREBP1 is known to play an important role in supporting lipid synthesis in cancer cells. Thus, we propose that the SREBP1-dependent regulation of cyclin D1 coordinates cell proliferation with the enhanced lipid synthesis required to support cell growth.
转录因子固醇调节元件结合蛋白（SREBP）家族调控胆固醇、脂肪酸及甘油三酯的合成与代谢。然而，它们也是主要肿瘤抑制因子泛素连接酶Fbw7的作用靶点，这表明它们可能调控细胞生长。事实上，脂质合成增强是许多人类肿瘤的一个标志。因此，SREBP途径最近已成为癌症治疗的一个潜在靶点。我们之前已经证明，这些转录因子之一SREBP1在有丝分裂期间会被稳定下来，并与靶启动子保持结合，这表明随着细胞进入G1期且转录恢复，这些靶基因的表达可能很重要。细胞周期蛋白D - cdk4/6复合物的激活对于转录抑制因子视网膜母细胞瘤蛋白（Rb）家族的磷酸化和失活以及细胞周期G1期的进展至关重要。重要的是，细胞周期蛋白D - cdk4/6 - Rb调控轴在人类癌症中经常失调。在当前的论文中，我们证明SREBP1通过与细胞周期蛋白D1启动子中的E - 盒结合来激活细胞周期蛋白D1的表达，细胞周期蛋白D1是cdk4和cdk6的共激活因子。因此，在人肝癌和乳腺癌细胞系中使SREBP1失活会降低细胞周期蛋白D1的表达并减弱Rb磷酸化。通过恢复细胞周期蛋白D1的表达可以挽救这些细胞中的Rb磷酸化。另一方面，活性SREBP1的表达以依赖于细胞周期蛋白D1和cdk4/6活性的方式诱导细胞周期蛋白D1的表达并增加Rb的磷酸化。SREBP1的失活导致细胞周期蛋白D1的表达降低、Rb磷酸化减弱以及增殖减少。SREBP1的失活还降低了细胞周期蛋白D1基因的胰岛素依赖性调节。同时，已知SREBP1在支持癌细胞中的脂质合成方面发挥重要作用。因此，我们提出SREBP1依赖性的细胞周期蛋白D1调节将细胞增殖与支持细胞生长所需的脂质合成增强相协调。
