Abstract
Vestigial-like 3 (VGLL3) is a member of the VGLL family, whose members serve as cofactors for TEA domain-containing transcription factors (TEADs). TEADs promote tissue and tumor development together with the cofactors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). Although VGLL3 is involved in tumor cell proliferation, its relationship with TEADs and YAP/TAZ remains largely unknown. To close this research gap, here we established tumor cells stably expressing VGLL3 and found that they exhibit enhanced proliferation. Notably, YAP and TAZ were inactivated in the VGLL3-expressing cells, coinciding with activation of the Hippo pathway, which suppresses YAP/TAZ activities. VGLL3 in combination with TEADs promoted expression of the Hippo pathway components large tumor suppressor kinase (LATS2) and angiomotin-like 2 (AMOTL2). VGLL3 was highly expressed in malignant breast tumor cells and osteosarcoma cells, and VGLL3 knockdown increased nuclear localization of YAP and TAZ. Knockdown of LATS2 or AMOTL2, as well as VGLL3 knockdown, repressed proliferation of breast tumor cells. Together, these results suggest that VGLL3 together with TEADs promotes cell proliferation by activating the Hippo pathway through LATS2 and AMOTL2, leading to YAP/TAZ inactivation.
Highlights
Vestigial-like 3 (VGLL3) is one of the four members of the vestigial-like (VGLL) family of proteins
Because Hippo pathway activation represses TEA domain–containing transcription factor (TEAD) activity, the cell growth–promoting effect of VGLL3 led us to speculate that VGLL3 inhibits the Hippo pathway and in turn induces nuclear translocation and activation of Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ)
Contrary to this speculation, components of the Hippo pathway, LATS2 and angiomotin-like 2 (AMOTL2), were increased, and YAP/TAZ were inactivated in VGLL3expressing cells
Summary
VGLL3 is one of the four members of the vestigial-like (VGLL) family of proteins. VGLL3 is thought to bind to TEA domain–containing transcription factors (TEADs) through the TONDU domain and function as a transcriptional cofactor for TEADs (1, 2). YAP/TAZ bind to TEADs in the nucleus and drive expression of target genes that are crucial for cell proliferation and survival. Given the involvement of VGLL3 in tumor development, it is possible that VGLL3 promotes cell growth by regulating TEADs and YAP/TAZ. TEADs bind to the GTIIC motif (59-ACATTCCA-39) in promoter regions and drive gene expression in association with YAP/TAZ (14–16).
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