4.6 Article

PCA3 controls chromatin organization and p53 signal activation by regulating LAP2 alpha-lamin A complexes

Journal

CANCER GENE THERAPY
Volume 29, Issue 3-4, Pages 358-368

Publisher

SPRINGERNATURE
DOI: 10.1038/s41417-021-00314-8

Keywords

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Funding

  1. JSPS [17K16809, 19K09698]
  2. Grants-in-Aid for Scientific Research [19K09698, 17K16809] Funding Source: KAKEN

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PCA3, a prostate cancer-specific lncRNA, promotes cancer progression by interacting with nucleoplasmic lamins via LAP2 alpha. Knockdown of PCA3 leads to changes in levels of HP1 gamma and histone modifications, as well as activation of the p53 signaling pathway and cell cycle arrest. These findings suggest a unique mechanism where PCA3 controls chromatin organization through regulation of nucleoplasmic lamins, potentially mediating cancer progression.
Prostate cancer antigen 3 (PCA3) is a prostate cancer-specific long noncoding RNA (lncRNA). Here, we report that lncRNA PCA3 plays a role in prostate cancer progression that is mediated by nucleoplasmic lamins. PCA3 interacts with the C-terminal region of lamina-associated polypeptide (LAP) 2 alpha. The C-terminal region of LAP2 alpha includes tumor suppressor protein retinoblastoma (pRb)- and lamin-binding domains, and it is necessary for the regulation and stabilization of the nucleoplasmic pool of lamin A. PCA3 inhibits the interaction of LAP2 alpha with lamin A through binding with the C-terminus of LAP2 alpha. The level of nucleoplasmic lamin A/C is increased by knockdown of PCA3. Together, the level of LAP2 alpha within the nucleus is increased by PCA3 knockdown. In PCA3 knockdown cells, the levels of HP1 gamma, trimethylation of Lys9 on histone H3 (H3K9me3), and trimethylation of Lys36 on histone H3 (H3K36me3)are upregulated. In contrast, trimethylation of Lys4 on histone H3 (H3K4me3) is downregulated. We further demonstrate that activation of the p53 signaling pathway and cell cycle arrest are promoted in the absence of PCA3. These findings support a unique mechanism in which prostate cancer-specific lncRNA controls chromatin organization via regulation of the nucleoplasmic pool of lamins. This proposed mechanism suggests that cancer progression may be mediated by nuclear lamins.

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