Histone lysine methyltransferase SETD8 promotes carcinogenesis by deregulating PCNA expression.

By M. Takawa, Hyun-soo Cho, S. Hayami, G. Toyokawa, Masaharu Kogure, Y. Yamane, Yukiko Iwai, Kazuhiro Maejima, K. Ueda, A. Masuda and 11 more. 2012

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Although the physiologic significance of lysine methylation of histones is well known, whether lysine methylation plays a role in the regulation of nonhistone proteins has not yet been examined. The histone lysine methyltransferase SETD8 is overexpressed in various types of cancer and seems to play a crucial role in S-phase progression. Here, we show that SETD8 regulates the function of proliferating cell nuclear antigen (PCNA) protein through lysine methylation. We found that SETD8 methylated PCNA on lysine 248, and either depletion of SETD8 or substitution of lysine 248 destabilized PCNA expression. Mechanistically, lysine methylation significantly enhanced the interaction between PCNA and the flap endonuclease FEN1. Loss of PCNA methylation retarded the maturation of Okazaki fragments, slowed DNA replication, and induced DNA damage, and cells expressing a methylation-inactive PCNA mutant were more susceptible to DNA damage. An increase of methylated PCNA was found in cancer cells, and the expression levels of SETD8 and PCNA were correlated in cancer tissue samples. Together, our findings reveal a function for lysine methylation on a nonhistone protein and suggest that aberrant lysine methylation of PCNA may play a role in human carcinogenesis.

Subfields: Molecular Biology

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Citations in the corpus

Dysregulation of AKT Pathway by SMYD2-Mediated Lysine Methylation on PTEN (2015, methodology): “In Vitro Methyltransferase Assay In vitro methyltransferase assays were described previously [17,19–22].”
Late Cornified Envelope Group I, a Novel Target of p53, Regulates PRMT5 Activity (2014, background): “Current progress of molecular medicine revealed that the enzymes relevant to histonemethylation play critical roles in human carcinogenesis [28,35–45].”
WHSC1 Promotes Oncogenesis through Regulation of NIMA-Related Kinase-7 in Squamous Cell Carcinoma of the Head and Neck (2014, methodology): “The assay was performed according to the manufacturer's instructions (7, 30, 31).”
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].”
SMYD2-dependent HSP90 methylation promotes cancer cell proliferation by regulating the chaperone complex formation. (2014, methodology): “293T cells were co-transfected with a FLAGSMYD2 expression vector and four different lengths of HA-HSP90AB1 vectors ([1–724], [1–500], [250–724] and [500–724]).”
Histone Modifications and Cancer. (2016, background): “hepatocellular carcinoma, and chronic myelogenous leukemia (Takawa et al. 2012)”
Protein lysine methyltransferase SMYD3 is involved in tumorigenesis through regulation of HER2 homodimerization (2017, methodology): “To investigate the biological significance of this methylation, we performed an ubiquitination assay as well as cycloheximide (CHX)chase analysis using the methods reported previously [26, 27], but we were unable to confirm polyubiquitination at this residue or found no evidence indicating the impor”
The histone methyltransferase SMYD2 methylates PARP1 and promotes poly(ADP-ribosyl)ation activity in cancer cells. (2014, background): “The accumulated evidence implicates deregulation of histone methylation appears to play crucial roles in human carcinogenesis [21]; for example, many lysine methyltransferases have been shown to function as oncogenes [22-26].”
PRMT1 promotes mitosis of cancer cells through arginine methylation of INCENP (2015, methodology): “In vitro methyltransferase assays were described previously [37, 39-46].”