Long non-coding RNA SNHG6 couples cholesterol sensing with mTORC1 activation in hepatocellular carcinoma
Long non-coding RNA SNHG6 couples cholesterol sensing with mTORC1 activation in hepatocellular carcinoma
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长非编码 RNA SNHG6 在肝细胞癌中将胆固醇传感与 mTORC1 激活结合起来。
DOI：
10.1038/s42255-022-00616-7
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发表时间：
2022-08-22
影响因子：
20.8
通讯作者：
Lin, Aifu
中科院分区：
文献类型：
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作者：
Liu, Fangzhou;Tian, Tian;Lin, Aifu
胆固醇稳态的改变可能有助于肝癌的侵袭性。Liu，Tian，and Zhang等人通过mTORC 1信号将胆固醇传感与癌细胞生长联系起来，确定了长链非编码RNA SNHG 6在这一过程中的重要作用。胆固醇有助于生物膜的结构基础，并作为信号分子发挥作用，其失调与各种人类疾病有关。在这里，我们报告了长链非编码RNA（lncRNA）SNHG 6通过调节胆固醇诱导的mTORC 1激活来增加从非酒精性脂肪性肝病（NAFLD）到肝细胞癌（HCC）的进展。在机制上，胆固醇结合ER锚定的FAF 2蛋白以促进SNHG 6-FAF 2-mTOR复合物的形成。作为一种假定的胆固醇效应子，SNHG 6通过增强ER-溶酶体接触处的FAF 2-mTOR相互作用来增强胆固醇依赖性mTORC 1溶酶体募集和激活，从而在自放大循环中协调mTORC 1激酶级联激活与细胞胆固醇生物合成，以加速胆固醇驱动的NAFLD-HCC发展。值得注意的是，SNHG 6的缺失抑制mTORC 1信号传导并损害患者来源的异种移植肝癌肿瘤的生长，从而将SNHG 6鉴定为肝癌治疗的潜在靶标。总之，我们的研究结果说明了细胞器相关lncRNA在细胞器通信，营养传感和激酶级联中的关键作用。
Alterations in cholesterol homeostasis may contribute to hepatic cancer aggressiveness. Liu, Tian, and Zhang et al. identify the long non-coding RNA SNHG6 as an important player in this process by linking cholesterol sensing with cancer cell growth through mTORC1 signaling.Cholesterol contributes to the structural basis of biological membranes and functions as a signaling molecule, whose dysregulation has been associated with various human diseases. Here, we report that the long non-coding RNA (lncRNA) SNHG6 increases progression from non-alcoholic fatty liver disease (NAFLD) to hepatocellular carcinoma (HCC) by modulating cholesterol-induced mTORC1 activation. Mechanistically, cholesterol binds ER-anchored FAF2 protein to promote the formation of a SNHG6-FAF2-mTOR complex. As a putative cholesterol effector, SNHG6 enhances cholesterol-dependent mTORC1 lysosomal recruitment and activation via enhancing FAF2-mTOR interaction at ER-lysosome contacts, thereby coordinating mTORC1 kinase cascade activation with cellular cholesterol biosynthesis in a self-amplified cycle to accelerate cholesterol-driven NAFLD-HCC development. Notably, loss of SNHG6 inhibits mTORC1 signaling and impairs growth of patient-derived xenograft liver cancer tumors, identifyifng SNHG6 as a potential target for liver cancer treatment. Together, our findings illustrate the crucial role of organelle-associated lncRNA in organelle communication, nutrient sensing, and kinase cascades.