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J. Biol. Chem. 287 (21): 17248-17256

© 2012 by The American Society for Biochemistry and Molecular Biology, Inc.

Background: Transcription factor Nkx3.1 is classically considered as an intracellular tumor suppressor.

Results: Nkx3.1 is intercellularly translocated for regulating gene expression and inhibiting prostate epithelial cell growth.

Conclusion: Nkx3.1 is a paracrine transcription factor mediating gene expression and growth inhibition signals between cells.

Significance: Transcription factors can be secreted and taken up among mammalian cells as a direct pathway for intercellular gene regulation.

Nkx3.1 Functions as Para-transcription Factor to Regulate Gene Expression and Cell Proliferation in Non-cell Autonomous Manner*

Jian Zhou{ddagger}1, Li Qin{ddagger}, Jean Ching-Yi Tien{ddagger}§, Li Gao{ddagger}, Xian Chen{ddagger}§, Fen Wang§, Jer-Tsong Hsieh||, , and Jianming Xu{ddagger}**2

From the {ddagger}Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030,
the §Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas 77030,
the Department of Urology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390,
the ||Graduate Institute of Cancer Biology, China Medical University Hospital, Taichung 40447, Taiwan, and
the **Luzhou Medical College, Luzhou, Sichuan 646000, China

ABSTRACT Back to Top

Abstract: Nkx3.1 is a homeoprotein transcription factor (TF) that inhibits proliferation of prostate epithelial cells (PECs) and acts as a tumor suppressor for prostate cancer (PCa). Because TFs classically function within the cells that produce them, Nkx3.1-induced growth inhibition was considered to occur in a cell-autonomous manner. We, however, found that Nkx3.1 protein can be secreted from cultured PECs and is detectable in the prostatic fluid and urine. A PCa-related point mutation (T164A) abolished Nkx3.1 secretion. Amazingly, secreted Nkx3.1 protein can translocate into adjacent cells, bind to the regulatory sequence of Nkx3.1 target genes and impact the expression of these genes in these adjacent cells. Expression of Nkx3.1 in PECs can also affect gene expression in adjacent cells, and this effect is abolished by the T164A mutation. Nkx3.1 protein inhibits cell proliferation when added to the culture. Expression of Nkx3.1, not the T164A mutant, also inhibits the proliferation of co-cultured cells. These results indicate that Nkx3.1 functions as a "para-transcription factor (PTF)," with the ability to regulate genes and inhibit cell proliferation in a non-cell autonomous manner. We also demonstrate that Nkx3.1 contains an evolutionarily conserved protein transduction domain essential for its PTF function, implicating potentially common PTF function among homeoproteins. In addition to the PCa-related T164A mutant, the secreted Nkx3.1 is reduced drastically in the prostatic fluid and urine of mice with PCa. These results indicate that Nkx3.1 can function as a PTF to suppress PCa and the urinary Nkx3.1 may be a potential biomarker for PCa diagnosis.

Key Words: Cell Cycle • Gene Regulation • Signal Transduction • Transcription Factors • Transcription Regulation • Tumor Suppressor Gene

Received for publication December 23, 2011. Revision received March 21, 2012.

1 To whom correspondence may be addressed: Dept. of Molecular and Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030. E-mail: jian.zhou{at}bcm.edu.

2 To whom correspondence may be addressed: Dept. of Molecular and Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030. E-mail: jxu{at}bcm.edu.

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