Abstract
PALI1 is a newly identified accessory protein of the Polycomb repressive complex 2 (PRC2) that catalyzes H3K27 methylation. However, the roles of PALI1 in cancer are yet to be defined. Here, we report that PALI1 is upregulated in advanced prostate cancer (PCa) and competes with JARID2 for binding to the PRC2 core subunit SUZ12. PALI1 further interacts with the H3K9 methyltransferase G9A, bridging the formation of a unique G9A-PALI1-PRC2 super-complex that occupies a subset of G9A-target genes to mediate dual H3K9/K27 methylation and gene repression. Many of these genes are developmental regulators required for cell differentiation, and their loss in PCa predicts poor prognosis. Accordingly, PALI1 and G9A drive PCa cell proliferation and invasion in vitro and xenograft tumor growth in vivo. Collectively, our study shows that PALI1 harnesses two central epigenetic mechanisms to suppress cellular differentiation and promote tumorigenesis, which can be targeted by dual EZH2 and G9A inhibition.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 4611-4626.e7 |
| Journal | Molecular cell |
| Volume | 82 |
| Issue number | 24 |
| DOIs | |
| State | Published - Dec 15 2022 |
Funding
GAL4-UAS-TK-Luc plasmid and pINTO-GAL4 cloning vector were gifts from Dr. Danny Reinberg (NYU). We thank Dr. Franco Au and Dr. Robert Qi (the Hong Kong University of Science and Technology) for their help with generating PALI1 antibodies. We thank Yohhei Takahashi (Northwestern University) for his assistance with the histone methyltransferase assay. We thank Galina Gritsina, Wanqing Xie, and Rakshitha Jagadish (Northwestern University) for helping with mice or PDX tissue IHC experiments. MS services were provided by the Taplin MS Facility, Harvard Medical School. Purification of PALI1 recombinant protein was conducted by the Recombinant Protein Production Core at Northwestern University. Next-generation Sequencing Services were done at the University of Chicago Genomics Facility. This work was supported in part by the American Cancer Society IRG-18-163-24 (to K.-w.F.), NIH P20GM121327 (to K.-w.F.), R03CA256230 (to K.-w.F.), prostate SPORE grant 5P50CA180995 (to J.Y.), R50CA211271 (J.C.Z.), R01CA172384 (to J.Y.), R01CA227918 (to J.Y.), and DOD grants PC160328 (to J.Y.) and PC160856 (to J.Y.). GAL4-UAS-TK-Luc plasmid and pINTO-GAL4 cloning vector were gifts from Dr. Danny Reinberg (NYU). We thank Dr. Franco Au and Dr. Robert Qi (the Hong Kong University of Science and Technology) for their help with generating PALI1 antibodies. We thank Yohhei Takahashi (Northwestern University) for his assistance with the histone methyltransferase assay. We thank Galina Gritsina, Wanqing Xie, and Rakshitha Jagadish (Northwestern University) for helping with mice or PDX tissue IHC experiments. MS services were provided by the Taplin MS Facility, Harvard Medical School. Purification of PALI1 recombinant protein was conducted by the Recombinant Protein Production Core at Northwestern University. Next-generation Sequencing Services were done at the University of Chicago Genomics Facility. This work was supported in part by the American Cancer Society IRG-18-163-24 (to K.-w.F.), NIH P20GM121327 (to K.-w.F.), R03CA256230 (to K.-w.F.), prostate SPORE grant 5P50CA180995 (to J.Y.), R50CA211271 (J.C.Z.), R01CA172384 (to J.Y.), R01CA227918 (to J.Y.), and DOD grants PC160328 (to J.Y.) and PC160856 (to J.Y.). J.Y. and K.-w.F. conceived the project and designed the experiments. K.-w.F. X.L. J.K. and A.P. performed wet-lab experiments. J.C.Z. conducted bioinformatics and statistical analysis. A.S. provided critical discussions of the project. J.Y. K.-w.F. and J.C.Z. generated the figures and wrote the manuscript. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research.
Keywords
- ChIP-seq
- Cut&Run
- EED
- EHMT1
- EHMT2
- ESC
- EZH2
- H3K27me3
- H3K9me2
- RNA-seq
- SUZ12
- histone methyltransferase
- prostate cancer
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology
