Vestigial-like family member 3 (VGLL3), a cofactor for TEAD transcription factors, promotes cancer cell proliferation by activating the Hippo pathway

Abstract

<jats:p>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.</jats:p>

Hybrid schwannoma–perineurioma frequently harbors VGLL3 rearrangement

“…Vestigial-like family member 3 ( VGLL3 ) is a member of the vestigial-like (VGLL) protein family, serving as a TEA domain–containing transcription factor (TEAD) cofactor ( 23 ). While its physiologic role is uncertain, it appears to promote cell proliferation through activation of the Hippo pathway ( 23 ); interestingly, it has been suggested to have a role in nerve formation and neural crest migration ( 24 ).…”

“…Vestigial-like family member 3 ( VGLL3 ) is a member of the vestigial-like (VGLL) protein family, serving as a TEA domain–containing transcription factor (TEAD) cofactor ( 23 ). While its physiologic role is uncertain, it appears to promote cell proliferation through activation of the Hippo pathway ( 23 ); interestingly, it has been suggested to have a role in nerve formation and neural crest migration ( 24 ). Amplification has been reported in myxoinflammatory fibroblastic sarcoma ( 14 , 25 , 26 ), along with several other sarcomas ( 27 ); however, to our knowledge, fusion genes involving VGLL3 have not previously been reported.…”

Multiple Roles of Vestigial-Like Family Members in Tumor Development

“…Recently, VGLL3 was found to promote proliferation of breast tumor and sarcoma cells by inducing LATS2 expression and Hippo pathway activation, suggesting that the Hippo pathway promotes tumor cell proliferation through inhibition of YAP/TAZ in the presence of VGLL3 ( 25 ). Notably, YAP/TAZ are known to function as a tumor suppressor via a cell-autonomous mechanism ( 60 – 62 ) and a non-cell-autonomous mechanism ( 63 ).…”

Up‐regulation of cofilin‐1 in cell senescence associates with morphological change and p27kip1‐mediated growth delay

“…The transcriptional enhancer factors domain (TEAD) protein family contains four isoforms (TEAD1/2/3/4), which are highly conserved in mammalian cells and are related to gene transcription during development and oncogenic activation (Zhou et al, 2016). TEAD proteins share a common TEA DNA binding domain, but their transcriptional activities are determined by bound co‐activators (Hori et al, 2020). The interaction between TEADs and the YAP/TAZ transcriptional coactivator is known to counteract the Hippo tumor suppressive pathway (Thompson, 2020).…”

“…TEAD proteins share a common TEA DNA binding domain, but their transcriptional activities are determined by bound co-activators (Hori et al, 2020). The interaction between TEADs and the YAP/ TAZ transcriptional coactivator is known to counteract the Hippo tumor suppressive pathway (Thompson, 2020).…”