LASS2 enhances p53 protein stability and nuclear import to suppress liver cancer progression through interaction with MDM2/MDMX.
LASS2 enhances p53 protein stability and nuclear import to suppress liver cancer progression through interaction with MDM2/MDMX.
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DOI：
10.1038/s41420-023-01709-2
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发表时间：
2023-11-14
影响因子：
7
通讯作者：
Yang, Yan
中科院分区：
文献类型：
--
作者：
Zhao, Qingqing;He, Wei;Liu, Zhouheng;Huang, Liangliang;Yang, Xiaoli;Liu, Yong;Chen, Rui;Min, Xun;Yang, Yan
LASS 2在肝细胞癌（HCC）中作为肿瘤抑制因子发挥作用，HCC是最常见的原发性肝癌类型，但其作用的潜在机制在很大程度上仍不清楚。此外，关于其在胆管癌（CCA）和肝母细胞瘤（HB）中的作用及其下游机制的详细报道很少。在本文中，发现LASS 2过表达显著抑制具有野生型（HB细胞系HepG 2）和突变的p53（HCC细胞系HCCLM 3和CCA细胞系HuCCT 1）的肝癌细胞的增殖、迁移、侵袭和诱导凋亡。基因集富集分析确定了LASS 2在p53信号通路中引起的差异表达基因的富集。LASS 2在HCC和CCA中的低表达与肿瘤的TNM分期有关，且与乙酰化p53（Lys 373）蛋白水平呈正相关。至少在某种程度上，LASS 2以p53依赖性方式发挥其肿瘤抑制作用，其中LASS 2与MDM 2/MDMX相互作用并引起双重抑制以破坏MDM 2/MDMX对p53的降解。此外，LASS 2诱导p53在ser 15处的磷酸化和在lys 373处的乙酰化，以促进从细胞质到细胞核的易位。这些发现为LASS 2诱导的肝癌肿瘤抑制机制提供了新的见解，并表明LASS 2可以作为肝癌的潜在治疗靶点。
LASS2 functions as a tumor suppressor in hepatocellular carcinoma (HCC), the most common type of primary liver cancer, but the underlying mechanism of its action remains largely unknown. Moreover, details on its role and the downstream mechanisms in Cholangiocarcinoma (CCA) and hepatoblastoma (HB), are rarely reported. Herein, LASS2 overexpression was found to significantly inhibit proliferation, migration, invasion and induce apoptosis in hepatoma cells with wild-type (HB cell line HepG2) and mutated p53 (HCC cell line HCCLM3 and CCA cell line HuCCT1). Gene set enrichment analysis determined the enrichment of the differentially expressed genes caused by LASS2 in the p53 signaling pathway. Moreover, the low expression of LASS2 in HCC and CCA tumor tissues was correlated with the advanced tumor-node-metastasis (TNM) stage, and the protein expression of LASS2 positively correlated with acetylated p53 (Lys373) protein levels. At least to some extent, LASS2 exerts its tumor-suppressive effects in a p53-dependent manner, in which LASS2 interacts with MDM2/MDMX and causes dual inhibition to disrupt p53 degradation by MDM2/MDMX. In addition, LASS2 induces p53 phosphorylation at ser15 and acetylation at lys373 to promote translocation from cytoplasm to nucleus. These findings provide new insights into the LASS2-induced tumor suppression mechanism in liver cancer and suggest LASS2 could serve as a potential therapeutic target for liver cancer.
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