RB1 methylation by SMYD2 enhances cell cycle progression through an increase of RB1 phosphorylation.

By Hyun-soo Cho, S. Hayami, G. Toyokawa, Kazuhiro Maejima, Y. Yamane, Takehiro Suzuki, N. Dohmae, Masaharu Kogure, Daechun Kang, David E. Neal and 4 more. 2012

196 citations recorded by the source corpus.

It is well known that RB functions are regulated by posttranslational modifications such as phosphorylation and acetylation, but the significance of lysine methylation on RB has not been fully elucidated. Our expression analysis of SMYD2 by quantitative real-time polymerase chain reaction showed that expression levels of SMYD2 are significantly elevated in human bladder carcinomas compared with nonneoplastic bladder tissues (P < .0001), and its expression levels in tumor tissues were much higher than those of any other normal tissues. SMYD2 knockdown resulted in the suppression of cancer cell growth, and cell cycle analysis indicated that SMYD2 might play a crucial role in the G(1)/S transition. According to an in vitro methyltransferase assay, we found that SMYD2 methylates RB1 protein, and liquid chromatography-tandem mass spectrometry analysis revealed lysine 810 of RB1 to be methylated by SMYD2. Importantly, this methylation enhanced Ser 807/811 phosphorylation of RB1 both in vitro and in vivo. Furthermore, we demonstrated that methylated RB1 accelerates E2F transcriptional activity and promotes cell cycle progression. SMYD2 is an important oncoprotein in various types of cancer, and SMYD2-dependent RB1 methylation at lysine 810 promotes cell cycle progression of cancer cells. Further study may explore SMYD2-dependent RB1 methylation as a potential therapeutic target in human cancer.

Subfields: Molecular Biology, Surgery

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Citations in the corpus

PRMT6 increases cytoplasmic localization of p21CDKN1A in cancer cells through arginine methylation and makes more resistant to cytotoxic agents (2015, background): “Even though whether PRMT6 methylates p21 in the nucleus or in the cytoplasm is still unknown, the present results imply that PRMT6 may play an important role in the functional regulation of not only histone proteins but also non-histone proteins as other histone methyltransferases [28–34].”
Overexpression of KDM5B/JARID1B is associated with poor prognosis in hepatocellular carcinoma (2018, unknown): “We have reported that various kinds of histone methyltransferases and demethylases may also contribute to human carcinogenesis [16–27].”
SMYD3-mediated lysine methylation in the PH domain is critical for activation of AKT1 (2016, unknown): “8, 10 mM dithiothreitol (DTT) and 10 mM MgCl 2 ), for 2 hours at 30°C [37–46].”
SUV39H2 methylates and stabilizes LSD1 by inhibiting polyubiquitination in human cancer cells (2015, methodology): “In vitro methyltransferase assays were performed as described previously [7, 44-50].”
The histone methyltransferase SMYD2 methylates PARP1 and promotes poly(ADP-ribosyl)ation activity in cancer cells. (2014, background): “Overexpression of SMYD2 was observed in various types of cancer [29,31].”
SMYD2-dependent HSP90 methylation promotes cancer cell proliferation by regulating the chaperone complex formation. (2014, background): “We recently demonstrated that SMYD2 was overexpressed in various types of cancer and played a crucial role in the cell cycle regulation of cancer cells through methylation of the tumor suppressor RB1 [14].”
PRMT1 promotes mitosis of cancer cells through arginine methylation of INCENP (2015, methodology): “In vitro methyltransferase assays were described previously [37, 39-46].”
Critical roles of SMYD2-mediated β-catenin methylation for nuclear translocation and activation of Wnt signaling (2017, background): “Our group has reported critical roles of SMYD2-mediated methylation in tumorigenesis as a methyltransferase [6-9].”
The histone methyltransferase SMYD2 is a novel therapeutic target for the induction of apoptosis in ovarian clear cell carcinoma cells (2020, background): “For instance, SMYD2 can methylate RB1 at Lys810, thereby modu‐ lating the cell cycle in bladder carcinoma (13).”
Dysregulation of AKT Pathway by SMYD2-Mediated Lysine Methylation on PTEN (2015, unknown): “Our present and previous studies demonstrated that SMYD2 is mainly localized in the cytoplasm (Figure 2A) [21,29,42], implying that the functionally important substrates of SMYD2 in human tumorigenesis may not be histone proteins but non-histone cytoplasmic proteins.”