The ZNF304-integrin axis protects against anoikis in cancer

Nat Commun. 2015 Jun 17;6:7351. doi: 10.1038/ncomms8351.

Burcu Aslan ¹ ² ³, Paloma Monroig ¹ ² ⁴, Ming-Chuan Hsu ⁵ ⁶, Guillermo Armaiz Pena ⁷, Cristian Rodriguez-Aguayo ¹ ³, Vianey Gonzalez-Villasana ¹, Rajesha Rupaimoole ² ⁷, Archana Sidalaghatta Nagaraja ² ⁷ ⁸, Selanere Mangala ³ ⁷, Hee-Dong Han ⁹, Erkan Yuca ¹⁰, Sherry Y Wu ⁷, Cristina Ivan ³ ⁷, Tyler J Moss ¹¹, Prahlad T Ram ¹¹, Huamin Wang ¹², Alexandra Gol-Chambers ¹, Ozgur Ozkayar ¹ ¹³, Pinar Kanlikilicer ¹, Enrique Fuentes-Mattei ¹², Nermin Kahraman ¹, Sunila Pradeep ⁷, Bulent Ozpolat ¹, Susan Tucker ¹⁴, Mien-Chie Hung ⁵ ¹⁵, Keith Baggerly ¹³, Geoffrey Bartholomeusz ¹, George Calin ¹ ³ ⁸, Anil K Sood ³ ⁷ ⁸, Gabriel Lopez-Berestein ¹ ³ ⁸

Affiliations

1 Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
2 Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
3 Center for RNA Interference and Non-Coding RNA, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
4 University of Puerto Rico School of Medicine, Reparto Metropolitano 1160 Ave Americano Miranda, San Juan 00936, Puerto Rico.
5 Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
6 National Institute of Cancer Research, National Health Research Institutes, No: 367, Shengli Road,Tainan City 704, Taiwan (ROC).
7 Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
8 Department of Cancer Biology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
9 Department of Immunology, School of Medicine, Konkuk University, 268 Chungwondaero,Chungcheongbukdo 380-701, South Korea.
10 Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
11 Department of Systems Biology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
12 Department of Pathology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
13 Department of Pathology, Hacettepe University School of Medicine, Ankara 06100, Turkey.
14 Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
15 Center for Molecular Medicine and Institute of Cancer Biology, China Medical University, No.91, Xueshi Road, Taichung City 404, Taiwan (ROC).

PMID: 26081979 DOI: 10.1038/ncomms8351

Abstract

Ovarian Cancer (OC) is a highly metastatic disease, but no effective strategies to target this process are currently available. Here, an integrative computational analysis of the Cancer Genome Atlas OC data set and experimental validation identifies a zinc finger transcription factor ZNF304 associated with OC metastasis. High tumoral ZNF304 expression is associated with poor overall survival in OC patients. Through reverse phase protein array analysis, we demonstrate that ZNF304 promotes multiple proto-oncogenic pathways important for cell survival, migration and invasion. ZNF304 transcriptionally regulates β1 Integrin, which subsequently regulates Src/focal adhesion kinase and paxillin and prevents anoikis. In vivo delivery of ZNF304 siRNA by a dual assembly nanoparticle leads to sustained gene silencing for 14 days, increased anoikis and reduced tumour growth in orthotopic mouse models of OC. Taken together, ZNF304 is a transcriptional regulator of β1 Integrin, promotes Cancer cell survival and protects against anoikis in OC.

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