The testis protein ZNF165 is a SMAD3 cofactor that coordinates oncogenic TGFβ signaling in triple-negative breast cancer.

ELife
Z. A. GibbsAngelique W Whitehurst

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.

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Datasets Mentioned

BETA
GSE63984
GSE63986
GSE65937
GSE130364

Methods Mentioned

BETA
xenograft
ChIP-seq
ChIP
nuclear translocation
transfection
immunoprecipitation
two-hybrid
proximity ligation
Profiler
ubiquitination

Software Mentioned

IGV browser
Bowtie2
Oncomine
HOMER
ImageJ
IHC Profiler
UALCAN
findPeaks
SAMtools
DepMap

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