BRAFV600E突变型结肠癌依赖基因UBE2N调节PTEN和INSIG泛素化促进胆固醇合成的机制研究

结肠癌是严重危害人类健康的恶性肿瘤，BRAF V600E突变结肠癌患者对现有的治疗手段反应不佳、预后更差。探索BRAF V600E突变结肠癌的相关机制及有效干预手段是亟待解决的问题。我们前期通过CRISPR/CAS9文库筛选发现UBE2N是BRAF V600E突变肠癌的依赖基因，并且可以通过影响胆固醇合成因子SREBP2促进了胆固醇合成，维持了BRAF V600E突变肠癌的增殖。然而，UBE2N调控SREBP2的机制尚不清楚。因此，本研究通过多种组学手段，阐明UBE2N促进BRAF V600E突变肠癌细胞的胆固醇合成，验证科学假设：UBE2N通过影响PTEN和INSIG的泛素化修饰，调节SREBP2的转录和翻译后激活促进胆固醇合成。本项目有望能揭示抗胆固醇合成是治疗BRAF V600E突变肿瘤的新方式。

Colon cancer is a serious malignance which has a heavy burden on public health, BRAF V600E mutated colon cancer patients response poorly to current treatment with a worse prognosis. It is a key and urgent issue to investigate the relevant mechanism and effective intervention for BRAF V600E mutated colon cancer patients. Our previous studies have shown UBE2N is a dependent gene based on CRISPR/CAS9 library screening, and promotes cholesterol biosynthesis via influencing the SREBP2, an important transcriptional factor in cholesterol biosynthesis and thus maintains the proliferation of BRAF V600E mutated colon cancer cells. However, the way that UBE2N regulates SREBP2 remains to be elucidated. Therefore, this study is intended to confirm that UBE2N promote cholesterol biosynthesis in BRAF V600E mutated colon cancer cells and testify that UBE2N modulates ubiquitination of PTEN and INSIG to regulate transcription and activation of SREBP2 to induce cholesterol biosynthesis. Our results may find anti-cholesterol biosynthesis could have a potential to treat BRAF V600E mutated colon cancer.