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Tang Q , Efe G , Chiarella AM , Leung J , Chen M , Yamazoe T , Su Z , Pitarresi JR , Li J , Islam M , Karakasheva T , Klein-Szanto AJ , Pan S , Hu J , Natsugoe S , Gu W , Stanger BZ , Wong KK , Diehl JA , Bass AJ , Nakagawa H , Murphy ME , Rustgi AK
Mutant p53 regulates Survivin to foster lung metastasis
Genes Dev. 2021 Mar 18
AbstractEsophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers worldwide and evolves often to lung metastasis. P53(R175H) (homologous to Trp53 (R172H) in mice) is a common hot spot mutation. How metastasis is regulated by p53(R175H) in ESCC remains to be investigated. To investigate p53(R175H)-mediated molecular mechanisms, we used a carcinogen-induced approach in Trp53(R172H/-) mice to model ESCC. In the primary Trp53(R172H/-) tumor cell lines, we depleted Trp53(R172H) (shTrp53) and observed a marked reduction in cell invasion in vitro and lung metastasis burden in a tail-vein injection model in comparing isogenic cells (shCtrl). Furthermore, we performed bulk RNA-seq to compare gene expression profiles of metastatic and primary shCtrl and shTrp53 cells. We identified the YAP-BIRC5 axis as a potential mediator of Trp53 (R172H) -mediated metastasis. We demonstrate that expression of Survivin, an antiapoptotic protein encoded by BIRC5, increases in the presence of Trp53(R172H) Furthermore, depletion of Survivin specifically decreases Trp53(R172H)-driven lung metastasis. Mechanistically, Trp53(R172H) but not wild-type Trp53, binds with YAP in ESCC cells, suggesting their cooperation to induce Survivin expression. Furthermore, Survivin high expression level is associated with increased metastasis in several GI cancers. Taken together, this study unravels new insights into how mutant p53 mediates metastasis.
Notes1549-5477 Tang, Qiaosi Efe, Gizem Chiarella, Anna M Leung, Jessica Orcid: 0000-0001-9682-9160 Chen, Maoting Yamazoe, Taiji Su, Zhenyi Pitarresi, Jason R Li, Jinyang Islam, Mirazul Karakasheva, Tatiana Klein-Szanto, Andres J Pan, Samuel Hu, Jianhua Natsugoe, Shoji Gu, Wei Stanger, Ben Z Orcid: 0000-0003-0410-4037 Wong, Kwok-K Diehl, J Alan Bass, Adam J Nakagawa, Hiroshi Murphy, Maureen E Rustgi, Anil K Journal Article United States Genes Dev. 2021 Mar 18. doi: 10.1101/gad.340505.120.