Details

Autor(en) / Beteiligte

• Shi, Chen
• Cai, Yong
• Li, Yongheng
• Li, Ye
• Hu, Nan
• Ma, Sai
• Hu, Shunying
• Zhu, Pingjun
• Wang, Weihu
• Zhou, Hao

Titel

Yap promotes hepatocellular carcinoma metastasis and mobilization via governing cofilin/F-actin/lamellipodium axis by regulation of JNK/Bnip3/SERCA/CaMKII pathways

Ist Teil von

• Redox biology, 2018-04, Vol.14, p.59-71

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2018

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Despite the increasingly important role of Hippo-Yap in hepatocellular carcinoma (HCC) development and progression, little insight is available at the time regarding the specifics interaction of Yap and cancer cells migration. Here, we identified the mechanism by which tumor-intrinsic Yap deletion resulted in HCC migratory inhibition. Yap was greatly upregulated in HCC and its expression promoted the cells migration. Functional studies found that knockdown of Yap induced JNK phosphorylation which closely bound to the Bnip3 promoter and contributed to Bnip3 expression. Higher Bnip3 employed excessive mitophagy leading to mitochondrial dysfunction and ATP shortage. The insufficient ATP inactivated SERCA and consequently triggered intracellular calcium overload. As the consequence of calcium oscillation, Ca/calmodulin-dependent protein kinases II (CaMKII) was signaled and subsequently inhibited cofilin activity via phosphorylated modification. The phosphorylated cofilin failed to manipulate F-actin polymerization and lamellipodium formation, resulting into the impairment of lamellipodium-based migration. Collectively, our results identified Hippo-Yap as the tumor promoter in hepatocellular carcinoma that mediated via activation of cofilin/F-actin/lamellipodium axis by limiting JNK-Bnip3-SERCA-CaMKII pathways, with potential application to HCC therapy involving cancer metastasis. [Display omitted] •Yap is upregulated in the hepatocellular carcinoma and promotes cancer cell migration.•Loss of Yap impairs cell mobility via inhibiting cofilin/F-actin/lamellipodium by activation of JNK-Bnip3-SERCA-CaMKII.•Loss of Yap enhances JNK phosphorylation which triggers Bnip3-required mitophagy.•Excessive mitophagy induces mitochondrial energy disorder which blunts SERCA and causes calcium overload.•The calcium overload drives CaMKII which inactivates cofilin, leading to F-actin degradation and lamellipodium collapse.