Zhang Kuangen, Wu Rui, Mei Fang, Zhou Yuhe, He Lin, Liu Yanhua, Zhao Xuyang, You Jiangfeng, Liu Beiying, Meng Qingyang, Pei Fei
Department of Pathology, Peking University Third Hospital, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
Department of Pathology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.
J Cell Biochem. 2021 Apr 14. doi: 10.1002/jcb.29926.
LASS2 is a novel tumor-suppressor gene and has been characterized as a ceramide synthase, which synthesizes very-long acyl chain ceramides. However, LASS2 function and pathway-related activity in prostate carcinogenesis are still largely unexplored. Here, we firstly report that LASS2 promotes β-catenin degradation through physical interaction with STK38, SCYL2, and ATP6V0C via the ubiquitin-proteasome pathway, phosphorylation of LASS2 is essential for β-catenin degradation, and serine residue 248 of LASS2 is illustrated to be a key phosphorylation site. Furthermore, we find that dephosphorylation of LASS2 at serine residue 248 significantly enhances prostate cancer cell growth and metastasis in vivo, indicating that phosphorylated LASS2 inhibits prostate carcinogenesis through negative regulation of Wnt/β-catenin signaling. Thus, our findings implicate LASS2 as a potential biomarker and therapeutic target of prostate cancer.
LASS2是一种新型肿瘤抑制基因，已被鉴定为一种神经酰胺合酶，可合成超长酰基链神经酰胺。然而，LASS2在前列腺癌发生中的功能及与通路相关的活性仍 largely 未被探索。在此，我们首先报道LASS2通过泛素-蛋白酶体途径与STK38、SCYL2和ATP6V0C进行物理相互作用来促进β-连环蛋白的降解，LASS2的磷酸化对于β-连环蛋白的降解至关重要，并且LASS2的丝氨酸残基248被证明是一个关键的磷酸化位点。此外，我们发现LASS2丝氨酸残基248的去磷酸化显著增强前列腺癌细胞在体内的生长和转移，表明磷酸化的LASS2通过对Wnt/β-连环蛋白信号通路的负调控来抑制前列腺癌发生。因此，我们的研究结果表明LASS2是前列腺癌的一种潜在生物标志物和治疗靶点。
