丢失LCMT1和有偏向性的蛋白磷酸酶2A异三聚体化推动前列腺癌的进展和治疗抵抗性。
Loss of LCMT1 and biased protein phosphatase 2A heterotrimerization drive prostate cancer progression and therapy resistance.
发表日期：2023 Aug 29
作者：
Reyaz Ur Rasool, Caitlin M O'Connor, Chandan Kanta Das, Mohammed Alhusayan, Brijesh Kumar Verma, Sehbanul Islam, Ingrid E Frohner, Qu Deng, Erick Mitchell-Velasquez, Jaya Sangodkar, Aqila Ahmed, Sarah Linauer, Ingrid Mudrak, Jessica Rainey, Kaitlin P Zawacki, Tahra K Suhan, Catherine G Callahan, Ryan Rebernick, Ramakrishnan Natesan, Javed Siddiqui, Guido Sauter, Dafydd Thomas, Shaomeng Wang, Derek J Taylor, Ronald Simon, Marcin Cieslik, Arul M Chinnaiyan, Luca Busino, Egon Ogris, Goutham Narla, Irfan A Asangani
来源：
Epigenetics & Chromatin
摘要：
缺失肿瘤抑制蛋白磷酸酶2A（PP2A）的活性与癌症有关，但其相关的分子机制尚不清楚。PP2A完整酶多由异二聚核心、支架A亚单位、催化C亚单位和超过20个不同底物定向调控B亚单位组成。C亚单位的甲基化调节PP2A异三聚体形成，影响B亚单位的结合和底物选择性。在本研究中，我们报告了亮氨酸羧甲基转移酶（LCMT1），该酶能够甲基化C亚单位的L309残基，并作为雄激素受体（AR）依赖的前列腺癌（PCa）的抑制剂。前列腺肿瘤中甲基化的PP2A-C水平降低与生化复发和转移相关。沉默LCMT1会增加AR的活性，并促进阉割抵抗性前列腺癌的生长。LCMT1依赖的甲基敏感AB56αCme异三聚体靶向AR及其关键共激活因子MED1进行去磷酸化，导致AR-MED1复合物从染色质中逐出，从而丧失靶基因表达。在机制上，LCMT1由S6K1介导的磷酸化诱导的β-TRCP调控，导致对抗雄激素的获得性耐药。最后，通过磷酸酶小分子激活剂（SMAP）的正反馈稳定作用，可以减弱AR信号和抑制抗雄激素耐药的前列腺癌的肿瘤生长。这些结果强调甲基化的PP2A-C作为预后标志物，LCMT1的丧失是AR依赖性前列腺癌的重要决定因素，暗示AR降解剂或PP2A调节剂在前列腺癌治疗中具有治疗潜力。© 2023. Springer Nature Limited.
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.© 2023. Springer Nature Limited.