HIPK1 drives p53 activation to limit colorectal cancer cell growth
Cell Cycle. 2013-06-15; 12(12): 1879-1891
DOI: 10.4161/cc.24927
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HIPK1 (homeodomain interacting protein kinase 1) is a serine/threonine kinase
that belongs to the CMGC superfamily. Emerging data point to the role of HIPK1 in
cancer, but it is still not clear whether it acts as a tumor suppressor or
promoter. Here we identified HIPK1 as a kinase that is significantly
overexpressed in colorectal cancer (CRC) and whose expression is stage-dependent.
Being abundantly expressed at the onset of the disease, the HIPK1 level gradually
decreased as tumor stage progressed. To further uncover how this factor regulates
tumorigenesis and establish whether it constitutes an early factor necessary for
neoplastic transformation or for cellular defense, we studied the effect of its
overexpression in vitro by investigating various cancer-related signaling
cascades. We found that HIPK1 mostly regulates the p53 signaling pathway both in
HCT116 and HeLa cells. By phosphorylating p53 on its serine-15, HIPK1 favored its
transactivation potential, which led to a rise in p21 protein level and a decline
in cell proliferation. Assuming that HIPK1 could impede CRC growth by turning on
the p53/p21 pathway, we then checked p21 mRNA levels in patients. Interestingly,
p21 transcripts were only increased in a subset of patients expressing high
levels of HIPK1. Unlike the rest of the cohort, the majority of these patients
hosted a native p53 protein, meaning that such a pro-survival pathway (HIPK1+ >
p53 > p21) is active in patients, and that HIPK1 acts rather as a tumor
suppressor.