Academic Journal
View in EDS

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

Bibliographic Details
Title: Loss of LCMT1 and biased protein phosphatase 2A heterotrimerization drive prostate cancer progression and therapy resistance.
Authors: Rasool, Reyaz ur, O'Connor, Caitlin M., Das, Chandan Kanta, Alhusayan, Mohammed, Verma, Brijesh Kumar, Islam, Sehbanul, Frohner, Ingrid E., Deng, Qu, Mitchell-Velasquez, Erick, Sangodkar, Jaya, Ahmed, Aqila, Linauer, Sarah, Mudrak, Ingrid, Rainey, Jessica, Zawacki, Kaitlin P., Suhan, Tahra K., Callahan, Catherine G., Rebernick, Ryan, Natesan, Ramakrishnan, Siddiqui, Javed
Source: Nature Communications; 8/29/2023, Vol. 14 Issue 1, p1-24, 24p
Subject Terms: PHOSPHOPROTEIN phosphatases, ANDROGEN receptors, PROSTATE cancer, CASTRATION-resistant prostate cancer, CANCER invasiveness, CANCER treatment
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. Loss of PP2A activity is often associated with cancer but the underlying mechanism remains unclear. Here, the authors show that decreased methylation of PP2A catalytic C subunit caused by loss of LCMT-1 in prostate cancer abrogates the tumor suppressor activity of PP2A on AR/MED1-dependent gene expression, proposing decreased methyl-PP2A-C as a prognostic marker for prostate cancer progression. [ABSTRACT FROM AUTHOR]
Copyright of Nature Communications is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Complementary Index
FullText Links:
  – Type: other
Text:
  Availability: 0
CustomLinks:
  – Url: https://login.libproxy.scu.edu/login?url=http://www.nature.com/openurl?genre=article&title=Nature%20Communications&volume=14&issue=1&spage=1
    Name: Nature Publishing
    Category: fullText
    Text: Full Text from Nature Publishing
    MouseOverText: Full Text from Nature Publishing
  – Url: https://resolver.ebsco.com/c/xy5jbn/result?sid=EBSCO:edb&genre=article&issn=20411723&ISBN=&volume=14&issue=1&date=20230829&spage=1&pages=1-24&title=Nature Communications&atitle=Loss%20of%20LCMT1%20and%20biased%20protein%20phosphatase%202A%20heterotrimerization%20drive%20prostate%20cancer%20progression%20and%20therapy%20resistance.&aulast=Rasool%2C%20Reyaz%20ur&id=DOI:10.1038/s41467-023-40760-6
    Name: Full Text Finder (for New FTF UI) (s8985755)
    Category: fullText
    Text: Find It @ SCU Libraries
    MouseOverText: Find It @ SCU Libraries
Header DbId: edb
DbLabel: Complementary Index
An: 170899486
RelevancyScore: 983
AccessLevel: 6
PubType: Academic Journal
PubTypeId: academicJournal
PreciseRelevancyScore: 983.145812988281
IllustrationInfo
Items – Name: Title
  Label: Title
  Group: Ti
  Data: Loss of LCMT1 and biased protein phosphatase 2A heterotrimerization drive prostate cancer progression and therapy resistance.
– Name: Author
  Label: Authors
  Group: Au
  Data: <searchLink fieldCode="AR" term="%22Rasool%2C+Reyaz+ur%22">Rasool, Reyaz ur</searchLink><br /><searchLink fieldCode="AR" term="%22O'Connor%2C+Caitlin+M%2E%22">O'Connor, Caitlin M.</searchLink><br /><searchLink fieldCode="AR" term="%22Das%2C+Chandan+Kanta%22">Das, Chandan Kanta</searchLink><br /><searchLink fieldCode="AR" term="%22Alhusayan%2C+Mohammed%22">Alhusayan, Mohammed</searchLink><br /><searchLink fieldCode="AR" term="%22Verma%2C+Brijesh+Kumar%22">Verma, Brijesh Kumar</searchLink><br /><searchLink fieldCode="AR" term="%22Islam%2C+Sehbanul%22">Islam, Sehbanul</searchLink><br /><searchLink fieldCode="AR" term="%22Frohner%2C+Ingrid+E%2E%22">Frohner, Ingrid E.</searchLink><br /><searchLink fieldCode="AR" term="%22Deng%2C+Qu%22">Deng, Qu</searchLink><br /><searchLink fieldCode="AR" term="%22Mitchell-Velasquez%2C+Erick%22">Mitchell-Velasquez, Erick</searchLink><br /><searchLink fieldCode="AR" term="%22Sangodkar%2C+Jaya%22">Sangodkar, Jaya</searchLink><br /><searchLink fieldCode="AR" term="%22Ahmed%2C+Aqila%22">Ahmed, Aqila</searchLink><br /><searchLink fieldCode="AR" term="%22Linauer%2C+Sarah%22">Linauer, Sarah</searchLink><br /><searchLink fieldCode="AR" term="%22Mudrak%2C+Ingrid%22">Mudrak, Ingrid</searchLink><br /><searchLink fieldCode="AR" term="%22Rainey%2C+Jessica%22">Rainey, Jessica</searchLink><br /><searchLink fieldCode="AR" term="%22Zawacki%2C+Kaitlin+P%2E%22">Zawacki, Kaitlin P.</searchLink><br /><searchLink fieldCode="AR" term="%22Suhan%2C+Tahra+K%2E%22">Suhan, Tahra K.</searchLink><br /><searchLink fieldCode="AR" term="%22Callahan%2C+Catherine+G%2E%22">Callahan, Catherine G.</searchLink><br /><searchLink fieldCode="AR" term="%22Rebernick%2C+Ryan%22">Rebernick, Ryan</searchLink><br /><searchLink fieldCode="AR" term="%22Natesan%2C+Ramakrishnan%22">Natesan, Ramakrishnan</searchLink><br /><searchLink fieldCode="AR" term="%22Siddiqui%2C+Javed%22">Siddiqui, Javed</searchLink>
– Name: TitleSource
  Label: Source
  Group: Src
  Data: Nature Communications; 8/29/2023, Vol. 14 Issue 1, p1-24, 24p
– Name: Subject
  Label: Subject Terms
  Group: Su
  Data: <searchLink fieldCode="DE" term="%22PHOSPHOPROTEIN+phosphatases%22">PHOSPHOPROTEIN phosphatases</searchLink><br /><searchLink fieldCode="DE" term="%22ANDROGEN+receptors%22">ANDROGEN receptors</searchLink><br /><searchLink fieldCode="DE" term="%22PROSTATE+cancer%22">PROSTATE cancer</searchLink><br /><searchLink fieldCode="DE" term="%22CASTRATION-resistant+prostate+cancer%22">CASTRATION-resistant prostate cancer</searchLink><br /><searchLink fieldCode="DE" term="%22CANCER+invasiveness%22">CANCER invasiveness</searchLink><br /><searchLink fieldCode="DE" term="%22CANCER+treatment%22">CANCER treatment</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: 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. Loss of PP2A activity is often associated with cancer but the underlying mechanism remains unclear. Here, the authors show that decreased methylation of PP2A catalytic C subunit caused by loss of LCMT-1 in prostate cancer abrogates the tumor suppressor activity of PP2A on AR/MED1-dependent gene expression, proposing decreased methyl-PP2A-C as a prognostic marker for prostate cancer progression. [ABSTRACT FROM AUTHOR]
– Name: Abstract
  Label:
  Group: Ab
  Data: <i>Copyright of Nature Communications is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
PLink https://login.libproxy.scu.edu/login?url=https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&scope=site&db=edb&AN=170899486
RecordInfo BibRecord:
  BibEntity:
    Identifiers:
      – Type: doi
        Value: 10.1038/s41467-023-40760-6
    Languages:
      – Code: eng
        Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 24
        StartPage: 1
    Subjects:
      – SubjectFull: PHOSPHOPROTEIN phosphatases
        Type: general
      – SubjectFull: ANDROGEN receptors
        Type: general
      – SubjectFull: PROSTATE cancer
        Type: general
      – SubjectFull: CASTRATION-resistant prostate cancer
        Type: general
      – SubjectFull: CANCER invasiveness
        Type: general
      – SubjectFull: CANCER treatment
        Type: general
    Titles:
      – TitleFull: Loss of LCMT1 and biased protein phosphatase 2A heterotrimerization drive prostate cancer progression and therapy resistance.
        Type: main
  BibRelationships:
    HasContributorRelationships:
      – PersonEntity:
          Name:
            NameFull: Rasool, Reyaz ur
      – PersonEntity:
          Name:
            NameFull: O'Connor, Caitlin M.
      – PersonEntity:
          Name:
            NameFull: Das, Chandan Kanta
      – PersonEntity:
          Name:
            NameFull: Alhusayan, Mohammed
      – PersonEntity:
          Name:
            NameFull: Verma, Brijesh Kumar
      – PersonEntity:
          Name:
            NameFull: Islam, Sehbanul
      – PersonEntity:
          Name:
            NameFull: Frohner, Ingrid E.
      – PersonEntity:
          Name:
            NameFull: Deng, Qu
      – PersonEntity:
          Name:
            NameFull: Mitchell-Velasquez, Erick
      – PersonEntity:
          Name:
            NameFull: Sangodkar, Jaya
      – PersonEntity:
          Name:
            NameFull: Ahmed, Aqila
      – PersonEntity:
          Name:
            NameFull: Linauer, Sarah
      – PersonEntity:
          Name:
            NameFull: Mudrak, Ingrid
      – PersonEntity:
          Name:
            NameFull: Rainey, Jessica
      – PersonEntity:
          Name:
            NameFull: Zawacki, Kaitlin P.
      – PersonEntity:
          Name:
            NameFull: Suhan, Tahra K.
      – PersonEntity:
          Name:
            NameFull: Callahan, Catherine G.
      – PersonEntity:
          Name:
            NameFull: Rebernick, Ryan
      – PersonEntity:
          Name:
            NameFull: Natesan, Ramakrishnan
      – PersonEntity:
          Name:
            NameFull: Siddiqui, Javed
    IsPartOfRelationships:
      – BibEntity:
          Dates:
            – D: 29
              M: 08
              Text: 8/29/2023
              Type: published
              Y: 2023
          Identifiers:
            – Type: issn-print
              Value: 20411723
          Numbering:
            – Type: volume
              Value: 14
            – Type: issue
              Value: 1
          Titles:
            – TitleFull: Nature Communications
              Type: main
ResultId 1