Stat3
is an oncogene frequently overexpressed in multiple cancers. Novel and Potential Methyl-Transferase (NPMT)
was first screened out as a stat3 target in our lab. It is an interesting
potential novel epigenetic enzyme as it can bind S-adenosyl-methionine and form
complex with histones, although the exact substrate is still unclear. Mutations
of NPMT were reported by cancer genome project in various cancers such as
melanoma and colon cancers, in which p53 is also frequently found as a driver
mutation. Coincidentally NPMT forms complex with p53 in co-immunoprecipitation
experiment. Human NPMT has three domains: an N-terminal SANT (Swi3,
Ada2, N-CoR and TFIIIB) domain which recruits p300 and binds
histone tails, a middle SAM binding domain for methyltransferase activity, and
a C-terminal NRB (nuclear receptor binding) motif. Additionally a pS/TQ motif
is located at very C-terminus and has been shown to be phosphorylated by ATM in response to irradiation. To elucidate
the function of NPMT, stable HCT116 colon cancer cells harboring mutation of
SANT, SAM or NRB domain of NPMT were established. Interestingly we found that
NPMT modulates the activation of ATM itself and its
downstream targets such as early DNA damage marker γH2AX, p53 tumor suppressor
in a manner dependent on the SAM binding ability of NPMT. As a result, G2/M
checkpoint was activated and led to growth arrest of cancer cell. Similar
results were observed with shRNAs against NPMT; however, dramatic effect
requires knockdown of both NPMT and its close member NPMT2 in the cell.
Clinical study in colorectal cancer patients showed a cohort with high p53 and
low NPMT level was correlated with higher survival rate, compared with cohort of
low p53 and high NPMT level. Our study revealed a novel connection between
Stat3-NPMT axis and ATM-p53 tumor suppressor pathway which could be attractive
therapeutic target in clinical study.
(Xinyu Liu and Junxin Liang contribute equally.)