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

Author

Listed:
  • Reyaz ur Rasool

    (University of Pennsylvania)

  • Caitlin M. O’Connor

    (University of Michigan
    University of Michigan)

  • Chandan Kanta Das

    (University of Pennsylvania)

  • Mohammed Alhusayan

    (University of Pennsylvania)

  • Brijesh Kumar Verma

    (University of Pennsylvania)

  • Sehbanul Islam

    (University of Pennsylvania)

  • Ingrid E. Frohner

    (Medical University of Vienna, Dr. Bohr-Gasse 9/2)

  • Qu Deng

    (University of Pennsylvania)

  • Erick Mitchell-Velasquez

    (University of Pennsylvania)

  • Jaya Sangodkar

    (University of Michigan
    University of Michigan)

  • Aqila Ahmed

    (University of Michigan
    University of Michigan)

  • Sarah Linauer

    (Medical University of Vienna, Dr. Bohr-Gasse 9/2)

  • Ingrid Mudrak

    (Medical University of Vienna, Dr. Bohr-Gasse 9/2)

  • Jessica Rainey

    (University of Pennsylvania)

  • Kaitlin P. Zawacki

    (University of Michigan
    University of Michigan)

  • Tahra K. Suhan

    (University of Michigan
    University of Michigan)

  • Catherine G. Callahan

    (University of Michigan
    University of Michigan)

  • Ryan Rebernick

    (University of Michigan Medical School
    University of Michigan)

  • Ramakrishnan Natesan

    (University of Pennsylvania)

  • Javed Siddiqui

    (University of Michigan Medical School
    University of Michigan)

  • Guido Sauter

    (University Medical Center Hamburg-Eppendorf)

  • Dafydd Thomas

    (University of Michigan)

  • Shaomeng Wang

    (University of Michigan)

  • Derek J. Taylor

    (Department of Biochemistry Case Western Reserve University School of Medicine)

  • Ronald Simon

    (University Medical Center Hamburg-Eppendorf)

  • Marcin Cieslik

    (University of Michigan Medical School
    University of Michigan)

  • Arul M. Chinnaiyan

    (University of Michigan Medical School
    University of Michigan)

  • Luca Busino

    (University of Pennsylvania)

  • Egon Ogris

    (Medical University of Vienna, Dr. Bohr-Gasse 9/2)

  • Goutham Narla

    (University of Michigan
    University of Michigan)

  • Irfan A. Asangani

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

Abstract

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.

Suggested Citation

  • 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 , 2023. "Loss of LCMT1 and biased protein phosphatase 2A heterotrimerization drive prostate cancer progression and therapy resistance," Nature Communications, Nature, vol. 14(1), pages 1-24, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40760-6
    DOI: 10.1038/s41467-023-40760-6
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    References listed on IDEAS

    as
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