Oncotarget

Research Papers:

KDM2A-dependent reduction of rRNA transcription on glucose starvation requires HP1 in cells, including triple-negative breast cancer cells

Kengo Okamoto, Yuji Tanaka, Sachiko Ogasawara, Chikashi Obuse, Jun-ichi Nakayama, Hirohisa Yano and Makoto Tsuneoka _

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Oncotarget. 2019; 10:4743-4760. https://doi.org/10.18632/oncotarget.27092

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Abstract

Kengo Okamoto1, Yuji Tanaka1, Sachiko Ogasawara2, Chikashi Obuse3, Jun-ichi Nakayama4, Hirohisa Yano2 and Makoto Tsuneoka1

1 Laboratory of Molecular and Cellular Biology, Faculty of Pharmacy, Takasaki University of Health and Welfare, Takasaki, Japan

2 Department of Pathology, Kurume University School of Medicine, Kurume, Japan

3 Department of Biological Sciences, Graduate School of Science, Osaka University, Osaka Japan

4 Division of Chromatin Regulation, National Institute for Basic Biology, Okazaki, Japan

Correspondence to:

Makoto Tsuneoka,email: tsuneoka@takasaki-u.ac.jp

Keywords: HP1; KDM2A; nucleoli; rRNA; TNBC

Received: February 27, 2019     Accepted: June 29, 2019     Published: July 30, 2019

ABSTRACT

Triple-negative breast cancer (TNBC) is very aggressive and lacks specific therapeutic targets. Ribosome RNAs (rRNAs) are central components of ribosomes and transcribed in nucleoli, and the level of rRNA transcription greatly affects ribosome production and cell proliferation. We have reported that an epigenetic protein, KDM2A, exists in nucleoli and reduces rRNA transcription on glucose starvation. However, the molecular mechanism is still unclear. The purpose of this study is to examine the KDM2A-dependent regulation mechanism of rRNA transcription. In this study, we turned our attention to the nucleolar accumulation of KDM2A. We found that KDM2A had multiple regions for its nucleolar localization, and one of the regions was directly bound by heterochromatin protein 1γ (HP1γ) using valine 801 in the LxVxL motif of KDM2A. A knockdown of HP1γ or a point mutation of valine 801 in KDM2A decreased the nucleolar accumulation of KDM2A, and suppressed the reduction of rRNA transcription on glucose starvation. These results uncovered a novel function of HP1γ: the regulation of rRNA transcription, and suggested that HP1γ stimulates the nucleolar accumulation of KDM2A to support the KDM2A-dependent regulation of rRNA transcription. HP1γ was expressed in cancer cells in all breast carcinoma tissues examined, including TNBC tissues. A knockdown of HP1γ in a TNBC cell line, MDA-MB-231 cells, reduced the nucleolar accumulation of KDM2A, and suppressed the reductions of rRNA transcription and cell proliferation on glucose starvation. These results suggest that the KDM2A-dependent regulation of rRNA transcription requires HP1γ, and thus may be applicable to the treatment of TNBC.


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