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Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15INK4B tumor suppressor gene

Oncogene volume 30, pages 1956–1962 (2011)Cite this article

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Abstract

A 42 kb region on human chromosome 9p21 encodes for three distinct tumor suppressors, p16INK4A, p14ARF and p15INK4B, and is altered in an estimated 30–40% of human tumors. The expression of the INK4A-ARF-INK4B gene cluster is silenced by polycomb during normal cell growth and is activated by oncogenic insults and during aging. How the polycomb is recruited to repress this gene cluster is unclear. Here, we show that expression of oncogenic Ras, which stimulates the expression of p15INK4B and p16INK4A, but not p14ARF, inhibits the expression of ANRIL (antisense non-coding RNA in the I NK4 locus), a 3.8 kb-long non-coding RNA expressed in the opposite direction from INK4A-ARF-INK4B. We show that the p15INK4B locus is bound by SUZ12, a component of polycomb repression complex 2 (PRC2), and is H3K27-trimethylated. Notably, depletion of ANRIL disrupts the SUZ12 binding to the p15INK4B locus, increases the expression of p15INK4B, but not p16INK4A or p14ARF, and inhibits cellular proliferation. Finally, RNA immunoprecipitation demonstrates that ANRIL binds to SUZ12 in vivo. Collectively, these results suggest a model in which ANRIL binds to and recruits PRC2 to repress the expression of p15INK4B locus.

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Acknowledgements

We thank Howard Chang for the insightful discussion during this study, Yaxue Zeng and Matt Smith for helpful discussion and reading the manuscript, Mika Matsumoto, Michiyo Hakamata and Harumi Shiratori for technical assistance. This study is supported by grants from the Ministry of Education, Science, Sports, Culture, and Technology of Japan (YK, MK, SS and KK) and NIH grant CA68377 (YX).

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Authors and Affiliations

  1. Department of Biochemistry 1, Hamamatsu University School of Medicine, Shizuoka, Japan

    Y Kotake, K Kitagawa, S Suzuki, N Liu & M Kitagawa

  2. Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, Program in Molecular Biology and Biotechnology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Y Kotake, T Nakagawa & Y Xiong

  3. Department of Biochemistry and Biophysics, Program in Molecular Biology and Biotechnology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Y Xiong

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  1. Y Kotake
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Correspondence to M Kitagawa or Y Xiong.

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Kotake, Y., Nakagawa, T., Kitagawa, K. et al. Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15INK4B tumor suppressor gene. Oncogene 30, 1956–1962 (2011). https://doi.org/10.1038/onc.2010.568

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