Demethylation of RB regulator MYPT1 by histone demethylase LSD1 promotes cell cycle progression in cancer cells

Hyun Soo Cho, Takehiro Suzuki, Naoshi Dohmae, Shinya Hayami, Motoko Unoki, Masanori Yoshimatsu, Gouji Toyokawa, Masashi Takawa, Taiping Chen, Julia K. Kurash, Helen I. Field, Bruce A.J. Ponder, Yusuke Nakamura, Ryuji Hamamoto

Research output: Contribution to journalArticle

109 Citations (Scopus)

Abstract

Histone demethylase LSD1 (also known as KDM1 and AOF2) is active in various cancer cells, but its biological significance in human carcinogenesis is unexplored. In this study, we explored hypothesized interactions between LSD1 and MYPT1, a known regulator of RB1 phosphorylation. We found that MYPT1 was methylated in vitro and in vivo by histone lysine methyltransferase SETD7 and demethylated by LSD1, identifying Lys 442 of MYPT1 as a target for methylation/demethylation by these enzymes. LSD1 silencing increased MYPT1 protein levels, decreasing the steady state level of phosphorylated RB1 (Ser 807/811) and reducing E2F activity. MYPT1 methylation status influenced the affinity of MYPT1 for the ubiquitin-proteasome pathway of protein turnover. MYPT1 was unstable in murine cells deficient in SETD7, supporting the concept that MYPT1 protein stability is physiologically regulated by methylation status. LSD1 overexpression could activate RB1 phosphorylation by inducing a destabilization of MYPT1 protein. Taken together, our results comprise a novel cell cycle regulatory mechanism mediated by methylation/demethylation dynamics, and they reveal the significance of LSD1 overexpression in human carcinogenesis.

Original languageEnglish
Pages (from-to)655-660
Number of pages6
JournalCancer Research
Volume71
Issue number3
DOIs
Publication statusPublished - Feb 1 2011

Fingerprint

Histone Demethylases
Methylation
Cell Cycle
Neoplasms
Histone-Lysine N-Methyltransferase
Carcinogenesis
Phosphorylation
Proteins
Protein Stability
Proteasome Endopeptidase Complex
Ubiquitin
Enzymes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Demethylation of RB regulator MYPT1 by histone demethylase LSD1 promotes cell cycle progression in cancer cells. / Cho, Hyun Soo; Suzuki, Takehiro; Dohmae, Naoshi; Hayami, Shinya; Unoki, Motoko; Yoshimatsu, Masanori; Toyokawa, Gouji; Takawa, Masashi; Chen, Taiping; Kurash, Julia K.; Field, Helen I.; Ponder, Bruce A.J.; Nakamura, Yusuke; Hamamoto, Ryuji.

In: Cancer Research, Vol. 71, No. 3, 01.02.2011, p. 655-660.

Research output: Contribution to journalArticle

Cho, HS, Suzuki, T, Dohmae, N, Hayami, S, Unoki, M, Yoshimatsu, M, Toyokawa, G, Takawa, M, Chen, T, Kurash, JK, Field, HI, Ponder, BAJ, Nakamura, Y & Hamamoto, R 2011, 'Demethylation of RB regulator MYPT1 by histone demethylase LSD1 promotes cell cycle progression in cancer cells', Cancer Research, vol. 71, no. 3, pp. 655-660. https://doi.org/10.1158/0008-5472.CAN-10-2446
Cho, Hyun Soo ; Suzuki, Takehiro ; Dohmae, Naoshi ; Hayami, Shinya ; Unoki, Motoko ; Yoshimatsu, Masanori ; Toyokawa, Gouji ; Takawa, Masashi ; Chen, Taiping ; Kurash, Julia K. ; Field, Helen I. ; Ponder, Bruce A.J. ; Nakamura, Yusuke ; Hamamoto, Ryuji. / Demethylation of RB regulator MYPT1 by histone demethylase LSD1 promotes cell cycle progression in cancer cells. In: Cancer Research. 2011 ; Vol. 71, No. 3. pp. 655-660.
@article{61c8a72e7b84491dad4fcc20b51e0a9d,
title = "Demethylation of RB regulator MYPT1 by histone demethylase LSD1 promotes cell cycle progression in cancer cells",
abstract = "Histone demethylase LSD1 (also known as KDM1 and AOF2) is active in various cancer cells, but its biological significance in human carcinogenesis is unexplored. In this study, we explored hypothesized interactions between LSD1 and MYPT1, a known regulator of RB1 phosphorylation. We found that MYPT1 was methylated in vitro and in vivo by histone lysine methyltransferase SETD7 and demethylated by LSD1, identifying Lys 442 of MYPT1 as a target for methylation/demethylation by these enzymes. LSD1 silencing increased MYPT1 protein levels, decreasing the steady state level of phosphorylated RB1 (Ser 807/811) and reducing E2F activity. MYPT1 methylation status influenced the affinity of MYPT1 for the ubiquitin-proteasome pathway of protein turnover. MYPT1 was unstable in murine cells deficient in SETD7, supporting the concept that MYPT1 protein stability is physiologically regulated by methylation status. LSD1 overexpression could activate RB1 phosphorylation by inducing a destabilization of MYPT1 protein. Taken together, our results comprise a novel cell cycle regulatory mechanism mediated by methylation/demethylation dynamics, and they reveal the significance of LSD1 overexpression in human carcinogenesis.",
author = "Cho, {Hyun Soo} and Takehiro Suzuki and Naoshi Dohmae and Shinya Hayami and Motoko Unoki and Masanori Yoshimatsu and Gouji Toyokawa and Masashi Takawa and Taiping Chen and Kurash, {Julia K.} and Field, {Helen I.} and Ponder, {Bruce A.J.} and Yusuke Nakamura and Ryuji Hamamoto",
year = "2011",
month = "2",
day = "1",
doi = "10.1158/0008-5472.CAN-10-2446",
language = "English",
volume = "71",
pages = "655--660",
journal = "Cancer Research",
issn = "0008-5472",
number = "3",

}

TY - JOUR

T1 - Demethylation of RB regulator MYPT1 by histone demethylase LSD1 promotes cell cycle progression in cancer cells

AU - Cho, Hyun Soo

AU - Suzuki, Takehiro

AU - Dohmae, Naoshi

AU - Hayami, Shinya

AU - Unoki, Motoko

AU - Yoshimatsu, Masanori

AU - Toyokawa, Gouji

AU - Takawa, Masashi

AU - Chen, Taiping

AU - Kurash, Julia K.

AU - Field, Helen I.

AU - Ponder, Bruce A.J.

AU - Nakamura, Yusuke

AU - Hamamoto, Ryuji

PY - 2011/2/1

Y1 - 2011/2/1

N2 - Histone demethylase LSD1 (also known as KDM1 and AOF2) is active in various cancer cells, but its biological significance in human carcinogenesis is unexplored. In this study, we explored hypothesized interactions between LSD1 and MYPT1, a known regulator of RB1 phosphorylation. We found that MYPT1 was methylated in vitro and in vivo by histone lysine methyltransferase SETD7 and demethylated by LSD1, identifying Lys 442 of MYPT1 as a target for methylation/demethylation by these enzymes. LSD1 silencing increased MYPT1 protein levels, decreasing the steady state level of phosphorylated RB1 (Ser 807/811) and reducing E2F activity. MYPT1 methylation status influenced the affinity of MYPT1 for the ubiquitin-proteasome pathway of protein turnover. MYPT1 was unstable in murine cells deficient in SETD7, supporting the concept that MYPT1 protein stability is physiologically regulated by methylation status. LSD1 overexpression could activate RB1 phosphorylation by inducing a destabilization of MYPT1 protein. Taken together, our results comprise a novel cell cycle regulatory mechanism mediated by methylation/demethylation dynamics, and they reveal the significance of LSD1 overexpression in human carcinogenesis.

AB - Histone demethylase LSD1 (also known as KDM1 and AOF2) is active in various cancer cells, but its biological significance in human carcinogenesis is unexplored. In this study, we explored hypothesized interactions between LSD1 and MYPT1, a known regulator of RB1 phosphorylation. We found that MYPT1 was methylated in vitro and in vivo by histone lysine methyltransferase SETD7 and demethylated by LSD1, identifying Lys 442 of MYPT1 as a target for methylation/demethylation by these enzymes. LSD1 silencing increased MYPT1 protein levels, decreasing the steady state level of phosphorylated RB1 (Ser 807/811) and reducing E2F activity. MYPT1 methylation status influenced the affinity of MYPT1 for the ubiquitin-proteasome pathway of protein turnover. MYPT1 was unstable in murine cells deficient in SETD7, supporting the concept that MYPT1 protein stability is physiologically regulated by methylation status. LSD1 overexpression could activate RB1 phosphorylation by inducing a destabilization of MYPT1 protein. Taken together, our results comprise a novel cell cycle regulatory mechanism mediated by methylation/demethylation dynamics, and they reveal the significance of LSD1 overexpression in human carcinogenesis.

UR - http://www.scopus.com/inward/record.url?scp=79551519643&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79551519643&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-10-2446

DO - 10.1158/0008-5472.CAN-10-2446

M3 - Article

C2 - 21115810

AN - SCOPUS:79551519643

VL - 71

SP - 655

EP - 660

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 3

ER -