Loss of LCMT1 and biased protein phosphatase 2A heterotrimerization drive prostate cancer progression and therapy resistance
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Published:2023-08-29
Issue:1
Volume:14
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Rasool Reyaz ur, O’Connor Caitlin M., Das Chandan Kanta, Alhusayan Mohammed, Verma Brijesh Kumar, Islam Sehbanul, Frohner Ingrid E.ORCID, Deng QuORCID, Mitchell-Velasquez Erick, Sangodkar Jaya, Ahmed Aqila, Linauer Sarah, Mudrak Ingrid, Rainey JessicaORCID, Zawacki Kaitlin P., Suhan Tahra K., Callahan Catherine G., Rebernick Ryan, Natesan Ramakrishnan, Siddiqui Javed, Sauter Guido, Thomas Dafydd, Wang Shaomeng, Taylor Derek J., Simon Ronald, Cieslik Marcin, Chinnaiyan Arul M.ORCID, Busino LucaORCID, Ogris Egon, Narla GouthamORCID, Asangani Irfan A.ORCID
Abstract
AbstractLoss 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.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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