Pin1, a conserved eukaryotic
peptidyl-prolyl cis/trans isomerase, has profound effects on numerous key-signaling molecules, and its deregulation contributes to disease, particularly
cancer. Although Pin1-mediated prolyl isomerization of
protein servers as a regulatory switch in signaling pathways, the significance of
proline isomerase activity in
chromatin modifying complex remains unclear. Here, we identify Pin1 as a key negative regulator for suppressor of variegation 3-9 homologue 1 (SUV39H1) stability, a major
methyltransferase responsible for
histone H3 trimethylation on Lys9 (H3K9me3). Pin1 interacts with SUV39H1 in a phosphorylation-dependent manner and promotes ubiquitination-mediated degradation of SUV39H1. Consequently, Pin1 reduces SUV39H1 abundance and suppresses SUV39H1 ability to induce H3K9me3. In contrast, depletion of Pin1 in
cancer cells leads to elevated SUV39H1 expression, which subsequently increases H3K9me3, inhibiting tumorigenecity of
cancer cells. In a xenograft model with 4T1 metastatic mouse
breast carcinoma cells, Pin1 overexpression increases
tumor growth, whereas SUV39H1 overexpression abrogates it. In human
breast cancer patients, immunohistochemical staining shows that Pin1 levels are negatively correlated with SUV39H1 as well as H3K9me3 levels. Thus, Pin1-mediated reduction of SUV39H1 stability contributes to convey oncogenic signals for aggressiveness of human
breast cancer, suggesting that Pin1 may be a promising
drug target for anticancer
therapy.