The testis protein ZNF165 is a SMAD3 cofactor that coordinates oncogenic TGFβ signaling in triple-negative breast cancer
- University of Texas Southwestern Medical Center, United States
Abstract
Cancer/testis (CT) antigens are proteins whose expression is normally restricted to germ cells yet aberrantly activated in tumors, where their functions remain relatively cryptic. Here we report that ZNF165, a CT antigen frequently expressed in triple-negative breast cancer (TNBC), associates with SMAD3 to modulate transcription of transforming growth factor β (TGFβ)-dependent genes and thereby promote growth and survival of human TNBC cells. In addition, we identify the KRAB zinc finger protein, ZNF446, and its associated tripartite motif protein, TRIM27, as obligate components of the ZNF165-SMAD3 complex that also support tumor cell viability. Importantly, we find that TRIM27 alone is necessary for ZNF165 transcriptional activity and is required for TNBC tumor growth in vivo using an orthotopic xenograft model in immunocompromised mice. Our findings indicate that aberrant expression of a testis-specific transcription factor is sufficient to co-opt somatic transcriptional machinery to drive a pro-tumorigenic gene expression program in TNBC.
Data availability
Data have been submitted under GEO access code GSE130364.
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Genomic binding profiles for ZNF165, ZNF446, and SMAD3 in triple-negative breast cancerNCBI Gene Expression Omnibus, GSE130364.
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ChIP-Seq analysis to identify direct binding of ZNF165NCBI Gene Expression Omnibus, GSE65937.
Article and author information
Author details
Angelique Whitehurst
Funding
National Cancer Institute (5R01CA196905)
- Zane A Gibbs
- Luis Reza
- Chun-chun Cheng
- Angelique Whitehurst
National Institute of General Medical Sciences (5T32GM007062)
- Zane A Gibbs
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (2016-101795) of UT-Southwestern. All surgery was performed under anesthesia, and every effort was made to minimize suffering.
Copyright
© 2020, Gibbs et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The testis protein ZNF165 is a SMAD3 cofactor that coordinates oncogenic TGFβ signaling in triple-negative breast cancer
eLife 9:e57679.
https://doi.org/10.7554/eLife.57679
