Liang L, Huan L, Wang J, et al, LncRNA RP11-295G20.2 regulates hepatocellular carcinoma cell growth and autophagy by targeting PTEN to lysosomal degradation, Cell Discov, 2021. (IF: 38.09)

Abstract: PTEN is a crucial tumor suppressor, and its loss is involved in various cancers. However, the detailed molecular mechanisms remain unclear, especially the involvement of lncRNAs. This study found that lncRNA RP11-295G20.2 is significantly upregulated in hepatocellular carcinoma (HCC) and promotes the growth of liver cancer cells both in vitro and in vivo. Furthermore, RP11-295G20.2 inhibits autophagy in liver cancer cells. Interestingly, RP11-295G20.2 directly binds to the PTEN protein and leads to its degradation. The expression of RP11-295G20.2 is inversely correlated with the expression of PTEN protein in 82 TCGA/TCPA-LIHC samples. Surprisingly, PTEN degradation induced by RP11-295G20.2 occurs through the lysosomal pathway instead of the proteasomal pathway. RP11-295G20.2 binds to the N-terminus of PTEN and facilitates the interaction of p62 with PTEN. Consequently, PTEN is translocated into lysosomes and degraded. RP11-295G20.2 also affects AKT phosphorylation and the translocation of FOXO3a into the nucleus, thereby regulating the transcription of autophagy-related genes. Collectively, RP11-295G20.2 directly binds to PTEN and enables its lysosomal degradation.

摘要：PTEN是一个关键的肿瘤抑制因子缺失涉及多种癌症，其详细分子机制仍然不清楚，尤其是lncRNAs的参与。本文研究发现lncRNA RP11-295G20.2在肝细胞癌中显著上调，并且在体外和体内促进肝癌细胞的生长。此外，RP11-295G20.2抑制肝癌细胞的自噬。有趣的是，RP11-295G20.2直接与PTEN蛋白结合并导致其降解。在82个TCGA/TCPA-LIHC样本中，RP11-295G20.2的表达与PTEN蛋白的表达呈负相关。令人惊讶的是，RP11-295G20.2诱导的PTEN降解是通过溶酶体途径而不是蛋白酶体途径。RP11-295G20.2与PTEN的N端结合，并促进p62与PTEN的相互作用。因此，PTEN被转运到溶酶体中并被降解。RP11-295G20.2还影响AKT的磷酸化和FOXO3a转移到细胞核，进而调节自噬相关基因的转录。总的来说，RP11-295G20.2直接与PTEN结合并使其在溶酶体中降解。这个新发现的RP11-295G20.2/PTEN轴揭示了肝癌中PTEN丢失的一个未被探索的分子机制。