LOC12调控脂代谢通路在肝细胞肝癌应对代谢应激及生长增殖中的作用及机制

Hepatocellular carcinoma (HCC) has high incidence, poor prognosis and limited effect of drug treatment. New targets for HCC treatment need to be found urgently. HCC is associated with lipid metabolism reprogramming, and investigation into dynamic regulation of lipid metabolism pathway can reveal the mechanism of response to metabolic stress and proliferation of HCC. It is reported that LOC12 is associated with resistance to Sorafenib of HCC, but more studies are needed to be carried out. Our previous data identified that LOC12 is overexpressed in HCC, promotes cell survival under metabolic stress and cell proliferation. Further, LOC12 regulates mRNA expression of a series of genes involving lipid metabolism pathway and leads to decreased lipid level under metabolic stress. Moreover, LOC12 promotes acetylation level of Histone H4 and interacts with NuA4 complex, which play a role in lipid homeostasis and stress response. With experiments in molecular, cell, mouse model and clinical tissues, our study would investigate the target gene network in lipid metabolism regulated by LOC12-NuA4 complex and its epigenetic mechanisms, analyze its function in stress response, cell survival and proliferation. Then we would reveal the role of LOC12 in responsing to metabolic stress, survival and proliferation of HCC cells, and may provide candidate target for clinical treatment.

肝细胞肝癌（HCC）的发病率高、预后差且现有的药物治疗效果有限，亟待发现新的治疗靶点。脂代谢重编程存在于HCC的发生发展过程中，研究脂代谢途径的动态调控能够揭示HCC应对代谢压力及生长增殖的具体机制。迄今为止，仅报道LOC12与HCC索拉菲尼耐药相关，其在HCC中更多的作用和机制有待研究。申请人的前期研究提示，LOC12在HCC中高表达、促进HCC细胞的生长增殖及在代谢应激环境下的存活;LOC12影响一系列脂代谢途径相关基因的表达并促进代谢应激环境下胞内脂质水平的降低。此外，LOC12促进组蛋白H4的乙酰化，并能结合参与脂质稳态调节及细胞应激反应的NuA4组蛋白乙酰化复合物。本项目拟在此基础上通过分子、细胞、动物模型及临床病例四个层面深入研究LOC12-NuA4复合物影响脂代谢的转录调控网络及表观遗传学机制，并分析其在应对代谢应激、促进肿瘤存活及生长增殖中的作用，为临床治疗提供候选靶标。

肝细胞肝癌（HCC）的发病率高、预后差且现有的药物治疗效果有限，亟待发现新的治疗靶点。脂代谢重编程存在于HCC的发生发展过程中，研究脂代谢途径的调控能够揭示HCC应对代谢压力及生长增殖的具体机制。LOC12全长172个氨基酸，含有与染色质重塑功能相关的SANT结构域。已有研究报道LOC12是NURF染色质重塑复合物及MLL1-WDR5组蛋白修饰复合物的组分之一，并能够通过表观遗传学机制影响一些核受体介导的基因转录调控，参与前列腺癌、乳腺癌及口腔鳞癌的发生和进展过程。本项目从分子细胞水平、动物模型和临床样本三个角度深入解析了LOC12在HCC中的表达情况、其靶基因网络及其靶基因调控的表观遗传机制。发现LOC12在HCC组织中的表达升高；明确了LOC12在HCC细胞中全基因组范围内的靶基因；证实了LOC12能够结合并调控PPARα介导的基因转录，其具体分子机制为LOC12能够招募NuA4复合物调节组蛋白H4的乙酰化修饰，从而影响相关基因的表达；LOC12能够在细胞水平及小鼠体内促进HCC细胞的生长增殖；并且LOC12能够促进HCC细胞的脂质含量及代谢应激下的细胞存活；此外，LOC12影响HCC细胞对索拉菲尼及仑伐替尼的敏感性及采用索拉菲尼治疗的患者预后。这些研究结果扩展了该因子在肿瘤中发挥作用的新机制，并为HCC的临床治疗提供实验依据。