Loss of LCMT1 and biased protein phosphatase 2A heterotrimerization drive prostate cancer progression and therapy resistance.

Autor:	Rasool RU; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, BRBII/III, Philadelphia, PA, 19104, USA., O'Connor CM; Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48105, USA.; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA., Das CK; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, BRBII/III, Philadelphia, PA, 19104, USA., Alhusayan M; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, BRBII/III, Philadelphia, PA, 19104, USA., Verma BK; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, BRBII/III, Philadelphia, PA, 19104, USA., Islam S; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, BRBII/III, Philadelphia, PA, 19104, USA., Frohner IE; Center for Medical Biochemistry, Max Perutz Labs, Medical University of Vienna, Dr. Bohr-Gasse 9/2, Vienna, 1030, Austria., Deng Q; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, BRBII/III, Philadelphia, PA, 19104, USA., Mitchell-Velasquez E; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, BRBII/III, Philadelphia, PA, 19104, USA., Sangodkar J; Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48105, USA.; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA., Ahmed A; Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48105, USA.; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA., Linauer S; Center for Medical Biochemistry, Max Perutz Labs, Medical University of Vienna, Dr. Bohr-Gasse 9/2, Vienna, 1030, Austria., Mudrak I; Center for Medical Biochemistry, Max Perutz Labs, Medical University of Vienna, Dr. Bohr-Gasse 9/2, Vienna, 1030, Austria., Rainey J; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, BRBII/III, Philadelphia, PA, 19104, USA., Zawacki KP; Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48105, USA.; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA., Suhan TK; Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48105, USA.; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA., Callahan CG; Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48105, USA.; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA., Rebernick R; Department of Pathology and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA.; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA., Natesan R; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, BRBII/III, Philadelphia, PA, 19104, USA., Siddiqui J; Department of Pathology and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA.; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA., Sauter G; Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany., Thomas D; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA., Wang S; Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA., Taylor DJ; Department of Biochemistry Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA., Simon R; Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany., Cieslik M; Department of Pathology and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA.; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA., Chinnaiyan AM; Department of Pathology and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA.; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA., Busino L; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, BRBII/III, Philadelphia, PA, 19104, USA., Ogris E; Center for Medical Biochemistry, Max Perutz Labs, Medical University of Vienna, Dr. Bohr-Gasse 9/2, Vienna, 1030, Austria. egon.ogris@meduniwien.ac.at., Narla G; Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48105, USA. gnarla@med.umich.edu.; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA. gnarla@med.umich.edu., Asangani IA; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, BRBII/III, Philadelphia, PA, 19104, USA. asangani@upenn.edu.; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. asangani@upenn.edu.; Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. asangani@upenn.edu.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2023 Aug 29; Vol. 14 (1), pp. 5253. Date of Electronic Publication: 2023 Aug 29.
DOI:	10.1038/s41467-023-40760-6
Abstrakt:	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.)
Databáze:	MEDLINE
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