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.
Nature communications. 2023 Aug 29*** epublish ***
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
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., Center for Medical Biochemistry, Max Perutz Labs, Medical University of Vienna, Dr. Bohr-Gasse 9/2, Vienna, 1030, Austria., Department of Pathology and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA., Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany., Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA., Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA., Department of Biochemistry Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA., Center for Medical Biochemistry, Max Perutz Labs, Medical University of Vienna, Dr. Bohr-Gasse 9/2, Vienna, 1030, Austria. ., Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48105, USA. ., Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, BRBII/III, Philadelphia, PA, 19104, USA. .