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Published on: March 27, 2020
VGLL4 Selectively Represses YAP-Dependent Gene Induction and Tumorigenic Phenotypes in Breast Cancer
Yinglong Zhang1,2, He Shen2, Henry G Withers2
1Department of Orthopedics, the First Affiliated Hospital of Chinese People's liberate Army General Hospital, Beijing, 100048, China.
Abstract:
Members of the mammalian Vestigial-like (VGLL) family of transcriptional cofactors activate genes in response to a wide variety of environmental cues. Recently, VGLL proteins have been proposed to regulate key signaling networks involved in cancer development and progression. However, the biological and clinical significance of VGLL dysregulation in human breast cancer pathogenesis remains unknown. Here, we report that diminished VGLL4 expression, but not VGLL1-3, correlated with both shorter relapse-free survival and shorter disease-specific survival of cancer patients with different molecular subtypes of breast cancer. Additionally, we further demonstrate that overexpression of VGLL4 reduces breast cancer cell proliferation, migration, intravasation/extravasation potential, favors cell death, and suppresses tumor growth in vivo. Mechanistically, VGLL4 negatively regulates the TEAD1-YAP1 transcriptional complex and exerts its growth inhibitory control through its evolutionary conserved TDU2 domain at its C-terminus. The results suggest that VGLL4 is a candidate tumor suppressor gene which acts by selectively antagonizing YAP-dependent tumor growth. VGLL4 may be a promising therapeutic target in breast cancer.
Insights
Reduced Vestigial-like (VGLL4) expression correlates with poor breast cancer survival. VGLL4 acts as a tumor suppressor by inhibiting YAP-dependent growth, suggesting it as a therapeutic target.
Area of Science:
- Molecular biology
- Cancer research
- Genetics
Background:
- Vestigial-like (VGLL) proteins are transcriptional cofactors involved in various biological processes.
- VGLL proteins are implicated in cancer development, but their role in breast cancer is unclear.
- Understanding VGLL family members' functions is crucial for cancer pathogenesis research.
Purpose of the Study:
- To investigate the biological and clinical significance of VGLL gene family dysregulation in human breast cancer.
- To determine the specific role of VGLL4 in breast cancer progression and tumor growth.
- To elucidate the molecular mechanisms underlying VGLL4's function in breast cancer.
Main Methods:
- Analysis of VGLL gene expression in breast cancer patient cohorts.
- Correlation of VGLL expression levels with patient survival data (relapse-free and disease-specific survival).
- In vitro studies assessing the effects of VGLL4 overexpression on breast cancer cell behavior (proliferation, migration, apoptosis).
- In vivo studies evaluating VGLL4's impact on tumor growth in animal models.
- Mechanistic studies investigating VGLL4's interaction with the TEAD1-YAP1 transcriptional complex.
Main Results:
- Diminished VGLL4 expression, unlike VGLL1-3, significantly correlated with shorter relapse-free and disease-specific survival across diverse breast cancer subtypes.
- Overexpression of VGLL4 suppressed breast cancer cell proliferation, migration, and intravasation/extravasation.
- VGLL4 overexpression promoted cancer cell death and inhibited tumor growth in vivo.
- VGLL4 negatively regulates the TEAD1-YAP1 transcriptional complex via its C-terminal TDU2 domain.
Conclusions:
- VGLL4 functions as a tumor suppressor gene in breast cancer.
- VGLL4 antagonizes YAP-dependent tumor growth, highlighting its critical role in regulating cancer progression.
- VGLL4 represents a potential therapeutic target for breast cancer treatment.
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