Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, BRBII/III, Philadelphia, PA, 19104, USA.
Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48105, USA.
Nat Commun. 2023 Aug 29;14(1):5253. doi: 10.1038/s41467-023-40760-6.
Loss of the tumor suppressive activity of the protein phosphatase 2A (PP2A) is associated with cancer, but the underlying molecular mechanisms are unclear. PP2A holoenzyme comprises a heterodimeric core, a scaffolding A subunit and a catalytic C subunit, and one of over 20 distinct substrate-directing regulatory B subunits. Methylation of the C subunit regulates PP2A heterotrimerization, affecting B subunit binding and substrate specificity. Here, we report that the leucine carboxy methyltransferase (LCMT1), which methylates the L309 residue of the C subunit, acts as a suppressor of androgen receptor (AR) addicted prostate cancer (PCa). Decreased methyl-PP2A-C levels in prostate tumors is associated with biochemical recurrence and metastasis. Silencing LCMT1 increases AR activity and promotes castration-resistant prostate cancer growth. LCMT1-dependent methyl-sensitive AB56αCme heterotrimers target AR and its critical coactivator MED1 for dephosphorylation, resulting in the eviction of the AR-MED1 complex from chromatin and loss of target gene expression. Mechanistically, LCMT1 is regulated by S6K1-mediated phosphorylation-induced degradation requiring the β-TRCP, leading to acquired resistance to anti-androgens. Finally, feedforward stabilization of LCMT1 by small molecule activator of phosphatase (SMAP) results in attenuation of AR-signaling and tumor growth inhibition in anti-androgen refractory PCa. These findings highlight methyl-PP2A-C as a prognostic marker and that the loss of LCMT1 is a major determinant in AR-addicted PCa, suggesting therapeutic potential for AR degraders or PP2A modulators in prostate cancer treatment.
蛋白磷酸酶 2A（PP2A）的肿瘤抑制活性丧失与癌症有关，但潜在的分子机制尚不清楚。PP2A 全酶由异源三聚体核心、支架 A 亚基和催化 C 亚基组成，以及 20 多个不同的底物定向调节 B 亚基之一。C 亚基的甲基化调节 PP2A 异三聚体化，影响 B 亚基结合和底物特异性。在这里，我们报告说，亮氨酸羧基甲基转移酶（LCMT1），它甲基化 C 亚基的 L309 残基，作为雄激素受体（AR）依赖型前列腺癌（PCa）的抑制剂。前列腺肿瘤中甲基化 PP2A-C 水平的降低与生化复发和转移有关。LCMT1 的沉默增加了 AR 活性，并促进了去势抵抗性前列腺癌的生长。LCMT1 依赖性甲基敏感 AB56αCme 异三聚体靶向 AR 和其关键共激活因子 MED1 进行去磷酸化，导致 AR-MED1 复合物从染色质中逐出，并丧失靶基因表达。从机制上讲，LCMT1 受 S6K1 介导的磷酸化诱导降解调控，需要β-TRCP，导致对雄激素拮抗剂的获得性耐药。最后，小分子磷酸酶激活剂（SMAP）的反馈稳定化导致 AR 信号转导的衰减和抗雄激素难治性 PCa 中的肿瘤生长抑制。这些发现强调了甲基化-PP2A-C 作为预后标志物的作用，以及 LCMT1 的丧失是 AR 依赖性 PCa 的主要决定因素，这表明 AR 降解剂或 PP2A 调节剂在前列腺癌治疗中有治疗潜力。
