Guangdong Provincial Key laboratory of Tumor Immunotherapy, School of Basic Medical Sciences, Cancer Research Institute, Southern Medical University, Guangzhou, 510632, China.
Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
Protein Cell. 2019 Aug;10(8):595-605. doi: 10.1007/s13238-019-0607-2. Epub 2019 Feb 1.
The E3 ligase HERC4 is overexpressed in human breast cancer and its expression levels correlated with the prognosis of breast cancer patients. However, the roles of HERC4 in mammary tumorigenesis remain unclear. Here we demonstrate that the knockdown of HERC4 in human breast cancer cells dramatically suppressed their proliferation, survival, migration, and tumor growth in vivo, while the overexpression of HERC4 promoted their aggressive tumorigenic activities. HERC4 is a new E3 ligase for the tumor suppressor LATS1 and destabilizes LATS1 by promoting the ubiquitination of LATS1. miRNA-136-5p and miRNA-1285-5p, expression of which is decreased in human breast cancers and is inversely correlated with the prognosis of breast cancer patients, are directly involved in suppressing the expression of HERC4. In summary, we discover a miRNA-HERC4-LATS1 pathway that plays important roles in the pathogenesis of breast cancer and represents new therapeutic targets for human breast cancer.
E3 连接酶 HERC4 在人乳腺癌中过表达，其表达水平与乳腺癌患者的预后相关。然而，HERC4 在乳腺肿瘤发生中的作用尚不清楚。在这里，我们证明了在人乳腺癌细胞中敲低 HERC4 显著抑制了它们的增殖、存活、迁移和体内肿瘤生长，而 HERC4 的过表达促进了它们侵袭性的致瘤活性。HERC4 是肿瘤抑制因子 LATS1 的一种新的 E3 连接酶，并通过促进 LATS1 的泛素化来使其不稳定。miRNA-136-5p 和 miRNA-1285-5p 的表达在人乳腺癌中降低，并且与乳腺癌患者的预后呈负相关，它们直接参与抑制 HERC4 的表达。总之，我们发现了一个 miRNA-HERC4-LATS1 通路，它在乳腺癌的发病机制中起着重要作用，代表了人类乳腺癌的新治疗靶点。
