Goel Hira Lal, Karner Emmet R, Kumar Ayush, Mukhopadhyay Dimpi, Goel Shivam, Mercurio Arthur M
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA.
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA.
J Biol Chem. 2024 Apr;300(4):107202. doi: 10.1016/j.jbc.2024.107202. Epub 2024 Mar 18.
We are interested in the contribution of integrins and the extracellular matrix to epithelial differentiation in carcinomas. This study was motivated by our finding that the Hippo effectors YAP and TAZ can sustain the expression of laminin 332 (LM332), the predominant ECM ligand for the integrin β4, in breast carcinoma cells with epithelial differentiation. More specifically, we observed that YAP and TAZ regulate the transcription of the LAMC2 subunit of LM332. Given that the β4-LM332 axis is associated with epithelial differentiation and YAP/TAZ have been implicated in carcinoma de-differentiation, we sought to resolve this paradox. Here, we observed that the β4 integrin sustains the expression of miR-200s that target the transcription factor ZEB1 and that ZEB1 has a pivotal role in determining the nature of YAP/TAZ-mediated transcription. In the presence of β4, ZEB1 expression is repressed enabling YAP/TAZ/TEAD-mediated transcription of LAMC2. The absence of β4, however, induces ZEB1, and ZEB1 binds to the LAMC2 promoter to inhibit LAMC2 transcription. YAP/TAZ-mediated regulation of LAMC2 has important functional consequences because we provide evidence that LM332 enables carcinoma cells to resist ferroptosis in concert with the β4 integrin.
我们对整合素和细胞外基质在癌上皮分化中的作用感兴趣。本研究的动机是我们发现，在具有上皮分化的乳腺癌细胞中，Hippo效应因子YAP和TAZ能够维持层粘连蛋白332（LM332）的表达，LM332是整合素β4的主要细胞外基质配体。更具体地说，我们观察到YAP和TAZ调节LM332的LAMC2亚基的转录。鉴于β4-LM332轴与上皮分化相关，且YAP/TAZ与癌去分化有关，我们试图解决这一矛盾。在此，我们观察到β4整合素维持靶向转录因子ZEB1的miR-200s的表达，并且ZEB1在决定YAP/TAZ介导的转录性质方面具有关键作用。在有β4的情况下，ZEB1表达受到抑制，从而使YAP/TAZ/TEAD介导LAMC2的转录。然而，缺乏β4会诱导ZEB1，并且ZEB1与LAMC2启动子结合以抑制LAMC2转录。YAP/TAZ介导的LAMC2调节具有重要的功能后果，因为我们提供的证据表明，LM332与β4整合素协同作用使癌细胞能够抵抗铁死亡。
