ZNF507 affects TGF-β signaling via TGFBR1 and MAP3K8 activation in the progression of prostate cancer to an aggressive state

Wookbong Kwon, Seong Kyoon Choi, Daehwan Kim, Hyeon Gyeom Kim, Jin Kyu Park, Jee Eun Han, Gil Jae Cho, Sungho Yun, Wookyung Yu, Se Hyeon Han, Yun Sok Ha, Jun Nyung Lee, Tae Gyun Kwon, Dong Hyung Cho, Jun Koo Yi, Myoung Ok Kim, Zae Young Ryoo, Song Park

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Background: The progression of prostate cancer (PC) to the highly aggressive metastatic castration-resistant prostate cancer (mCRPC) or neuroendocrine prostate cancer (NEPC) is a fatal condition and the underlying molecular mechanisms are poorly understood. Here, we identified the novel transcriptional factor ZNF507 as a key mediator in the progression of PC to an aggressive state. Methods: We analyzed ZNF507 expression in the data from various human PC database and high-grade PC patient samples. By establishment of ZNF507 knockdown and overexpression human PC cell lines, we assessed in vitro PC phenotype changes including cell proliferation, survival, migration and invasion. By performing microarray with ZNF507 knockdown PC cells, we profiled the gene clusters affected by ZNF507 knockdown. Moreover, ZNF507 regulated key signal was evaluated by dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays. Finally, we performed xenograft and in vivo metastasis assay to confirm the effect of ZNF507 knockdown in PC cells. Results: We found that ZNF507 expression was increased, particularly in the highly graded PC. ZNF507 was also found to be associated with metastatic PC of a high grade. Loss- or gain-of-function–based analysis revealed that ZNF507 promotes the growth, survival, proliferation, and metastatic properties of PC (e.g., epithelial-mesenchymal transition) by upregulating TGF-β signaling. Profiling of gene clusters affected by ZNF507 knockdown revealed that ZNF507 positively regulated the transcription of TGFBR1, MAP3K8, and FURIN, which in turn promoted the progression of PC to highly metastatic and aggressive state. Conclusions: Our findings suggest that ZNF507 is a novel key regulator of TGF-β signaling in the progression of malignant PC and could be a promising target for studying the development of advanced metastatic PCs.

Original languageEnglish
Article number291
JournalJournal of Experimental and Clinical Cancer Research
Volume40
Issue number1
DOIs
StatePublished - Dec 2021

Bibliographical note

Publisher Copyright:
© 2021, The Author(s).

Keywords

  • Metastasis
  • Prostate cancer
  • TGF-β signal
  • ZNF507
  • mCRPC

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