Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
Oncogene. 2013 Mar 21;32(12):1488-96. doi: 10.1038/onc.2012.178. Epub 2012 May 14.
Emerging evidence demonstrates that RUNX3 is a tumor suppressor in breast cancer. Inactivation of RUNX3 in mice results in spontaneous mammary gland tumors, and decreased or silenced expression of RUNX3 is frequently found in breast cancer cell lines and human breast cancer samples. However, the underlying mechanism for initiating RUNX3 inactivation in breast cancer remains elusive. Here, we identify prolyl isomerase Pin1, which is often overexpressed in breast cancer, as a key regulator of RUNX3 inactivation. In human breast cancer cell lines and breast cancer samples, expression of Pin1 inversely correlates with the expression of RUNX3. In addition, Pin1 recognizes four phosphorylated Ser/Thr-Pro motifs in RUNX3 via its WW domain. Binding of Pin1 to RUNX3 suppresses the transcriptional activity of RUNX3. Furthermore, Pin1 reduces the cellular levels of RUNX3 in an isomerase activity-dependent manner by inducing the ubiquitination and proteasomal degradation of RUNX3. Knocking down Pin1 enhances the cellular levels and transcriptional activity of RUNX3 by inhibiting the ubiquitination and degradation of RUNX3. Our results identify Pin1 as a new regulator of RUNX3 inactivation in breast cancer.
越来越多的证据表明 RUNX3 是乳腺癌的肿瘤抑制因子。RUNX3 在小鼠中的失活会导致自发性乳腺肿瘤，并且在乳腺癌细胞系和人乳腺癌样本中经常发现 RUNX3 的表达减少或沉默。然而，引发乳腺癌中 RUNX3 失活的潜在机制仍不清楚。在这里，我们确定脯氨酰异构酶 Pin1 是一种关键的 RUNX3 失活调节因子，它在乳腺癌中经常过表达。在人乳腺癌细胞系和乳腺癌样本中，Pin1 的表达与 RUNX3 的表达呈负相关。此外，Pin1 通过其 WW 结构域识别 RUNX3 中的四个磷酸化 Ser/Thr-Pro 基序。Pin1 与 RUNX3 的结合抑制了 RUNX3 的转录活性。此外，Pin1 通过诱导 RUNX3 的泛素化和蛋白酶体降解，以依赖于异构酶活性的方式降低细胞内 RUNX3 的水平。敲低 Pin1 通过抑制 RUNX3 的泛素化和降解来提高细胞内 RUNX3 的水平和转录活性。我们的结果表明 Pin1 是乳腺癌中 RUNX3 失活的一个新调节因子。
