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

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 () and Irfan A. Asangani ()
Additional contact information
Reyaz ur Rasool: University of Pennsylvania
Caitlin M. O’Connor: 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
Aqila Ahmed: 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
Tahra K. Suhan: University of Michigan
Catherine G. Callahan: University of Michigan
Ryan Rebernick: University of Michigan Medical School
Ramakrishnan Natesan: University of Pennsylvania
Javed Siddiqui: University of Michigan Medical School
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
Arul M. Chinnaiyan: University of Michigan Medical School
Luca Busino: University of Pennsylvania
Egon Ogris: Medical University of Vienna, Dr. Bohr-Gasse 9/2
Goutham Narla: University of Michigan
Irfan A. Asangani: University of Pennsylvania

Nature Communications, 2023, vol. 14, issue 1, 1-24

Abstract: 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.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-40760-6 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40760-6

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-40760-6

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().