Demethylation of RB Regulator MYPT1 by Histone Demethylase LSD1 Promotes Cell Cycle Progression in Cancer Cells

• Published in: Cancer research (Chicago, Ill.) Vol. 71; no. 3; pp. 655 - 660
• Main Authors: CHO, Hyun-Soo, SUZUKI, Takehiro, FIELD, Helen I, PONDER, Bruce A. J, NAKAMURA, Yusuke, HAMAMOTO, Ryuji, DOHMAE, Naoshi, HAYAMI, Shinya, UNOKI, Motoko, YOSHIMATSU, Masanori, TOYOKAWA, Gouji, TAKAWA, Masashi, TAIPING CHEN, KURASH, Julia K
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-02-2011
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Cancer; Cell Cycle - physiology; Histone Demethylases - metabolism; Humans; Medical sciences; Methylation; Mice; Myosin-Light-Chain Kinase - metabolism; Myosin-Light-Chain Phosphatase - metabolism; Neoplasms - enzymology; Neoplasms - pathology; Oxidoreductases, N-Demethylating - metabolism; Pharmacology. Drug treatments; Retinoblastoma Protein - metabolism; Tumors; Rb protein; Demethylation; Retinoblastoma gene; Cell cycle; Tumor progression; Regulator; Metabolism; Pharmacokinetics; Histone; Tumor cell; Tumor suppressor gene
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-10-2446

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.