Transcription factor POU4F2 promotes colorectal cancer cell migration and invasion through hedgehog-mediated epithelial-mesenchymal transition.

Abstract

As a POU homeodomain transcription factor, POU4F2 has been implicated in regulating tumorigenic processes in various cancers. However, the role of POU4F2 in colorectal cancer (CRC) remains unclear. Here, we revealed that POU4F2 functions as a tumor promotor in CRC. Bioinformatics analysis in specimens from CRC patients and expression analysis in CRC cell lines showed that POU4F2 was upregulated at the mRNA and protein levels in CRC. Depletion of POU4F2 suppressed the metastatic phenotypes of CRC cells, including cell migration, invasion, and the expression of epithelial-mesenchymal transition (EMT) markers. Moreover, depletion of POU4F2 decreased the number of lung metastatic nodes in nude mice. Mechanistically, POU4F2 positively regulated the Hedgehog signaling pathway, as inferred from the downregulation of the expression of sonic Hedgehog homolog, patched 1, Smoothened, and GLI family zinc finger 1 in vitro and vivo following silencing of POU4F2. Furthermore, the SMO agonist SAG reversed the effects of POU4F2 knockdown in CRC. Functionally, POU4F2 contributed to the Hedgehog signaling-regulated activation of the EMT process and promotion of CRC cell migration and invasion. Collectively, these findings elucidated the role of POU4F2 as a tumor promotor in CRC through the regulation of Hedgehog signaling-mediated EMT and suggested that POU4F2 suppression might be a promising therapeutic target in inhibiting CRC metastasis.

• Authors: Kaibo Guo, Peipei Wang, Leyin Zhang, Yiwen Zhou, Xinyang Dai, Yici Yan, Yuxuan Chen, Harpreet S Wasan, Jieru Yu, Shanming Ruan, Leitao Sun
• Journal: Cancer science (Cancer Sci) Vol. 112 Issue 10 Pg. 4176-4186 (Oct 2021) ISSN: 1349-7006 [Electronic] England
• PMID: 34327778 (Publication Type: Journal Article)
• Copyright: © 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• Cyclohexylamines
• Hedgehog Proteins
• Patched-1 Receptor
• RNA, Messenger
• RNA, Small Interfering
• SAG compound
• Smoothened Receptor
• Thiophenes
• Transcription Factor Brn-3B

Topics

• Animals
• Cell Line, Tumor
• Cell Movement
• Colon (metabolism, pathology)
• Colorectal Neoplasms (metabolism, pathology)
• Cyclohexylamines (pharmacology)
• Down-Regulation
• Epithelial-Mesenchymal Transition (physiology)
• Gene Silencing
• Hedgehog Proteins (metabolism)
• Humans
• Lung Neoplasms (secondary)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Molecular Targeted Therapy
• Neoplasm Invasiveness
• Patched-1 Receptor (metabolism)
• RNA, Messenger (metabolism)
• RNA, Small Interfering (metabolism)
• Signal Transduction
• Smoothened Receptor (agonists, metabolism)
• Thiophenes (pharmacology)
• Transcription Factor Brn-3B (antagonists & inhibitors, genetics, metabolism, physiology)
• Up-Regulation
• Zinc Fingers