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PCA3 controls chromatin organization and p53 signal activation by regulating LAP2α-lamin A complexes

Cancer Gene Therapy volume 29, pages 358–368 (2022)Cite this article

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Abstract

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) 2α. The C-terminal region of LAP2α 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 LAP2α with lamin A through binding with the C-terminus of LAP2α. The level of nucleoplasmic lamin A/C is increased by knockdown of PCA3. Together, the level of LAP2α within the nucleus is increased by PCA3 knockdown. In PCA3 knockdown cells, the levels of HP1γ, 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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Fig. 1: Interaction of PCA3 with LAP2α.
Fig. 2: PCA3 inhibits interaction of LAP2α with lamin A.
Fig. 3: Upregulation of nucleoplasmic lamin A/C and LAP2α by PCA3 knockdown.
Fig. 4: Chromatin abnormalities in PCA3 knockdown cells.
Fig. 5: Activation of p53 signaling by knockdown of PCA3.
Fig. 6: Knockdown of PCA3 reduced cell proliferation of prostate cancer cells.

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Acknowledgements

The authors would like to thank Ms. Kyoko Shimizu and Ms. Yukako Morioka for technical assistance.

Funding

This work was supported in part by JSPS (Grant-in-Aid for Scientific Research, Numbers 17K16809 and 19K09698).

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Authors and Affiliations

  1. Department of Urology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto-City, Kyoto, Japan

    Saya Ito, Takashi Ueda, Atsuko Fujihara, Fumiya Hongo & Osamu Ukimura

  2. Department of Molecular Endocrinology, Tohoku University Graduate School of Medicine, Sendai-City, Miyagi, Japan

    Atsushi Yokoyama

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  1. Saya Ito
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Correspondence to Saya Ito.

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Ito, S., Ueda, T., Yokoyama, A. et al. PCA3 controls chromatin organization and p53 signal activation by regulating LAP2α-lamin A complexes. Cancer Gene Ther 29, 358–368 (2022). https://doi.org/10.1038/s41417-021-00314-8

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