Matrix Stiffness Regulates TGFβ1‐Induced αSMA Expression via a G9a‐LATS‐YAP Signaling Cascade
ABSTRACT Extracellular matrix stiffness is enhanced in cancer and fibrosis; however, there is limited knowledge on how matrix mechanics modulate expression and signaling of the methyltransferase G9a. Here, we show that matrix stiffness and transforming growth factor (TGF)‐β1 signaling together regul...
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| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2025-07-01
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| Series: | FASEB BioAdvances |
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| Online Access: | https://doi.org/10.1096/fba.2025-00117 |
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| author | Chinmay S. Sankhe Jessica L. Sacco Victoria L. Crunkleton Malcom Díaz García Matthew J. Bierowski David Vidotto Rezende Soares Jacob A. Karnick Rachel L. Cecco Arefeh Abbasi Joy Kirigo Thomas K. Wood Esther W. Gomez |
| author_facet | Chinmay S. Sankhe Jessica L. Sacco Victoria L. Crunkleton Malcom Díaz García Matthew J. Bierowski David Vidotto Rezende Soares Jacob A. Karnick Rachel L. Cecco Arefeh Abbasi Joy Kirigo Thomas K. Wood Esther W. Gomez |
| author_sort | Chinmay S. Sankhe |
| collection | DOAJ |
| description | ABSTRACT Extracellular matrix stiffness is enhanced in cancer and fibrosis; however, there is limited knowledge on how matrix mechanics modulate expression and signaling of the methyltransferase G9a. Here, we show that matrix stiffness and transforming growth factor (TGF)‐β1 signaling together regulate G9a expression and the levels of the histone mark H3K9me2. Suppressing the activity and expression of G9a attenuates TGFβ1‐induced alpha smooth muscle actin (αSMA) and N‐cadherin expression and cell morphology changes in mammary epithelial cells cultured on stiff substrata. Knockdown of G9a increases the expression of large tumor suppressor kinase 2 (LATS2) and decreases the nuclear localization of yes associated protein (YAP). Furthermore, inhibition of LATS promotes an increase in YAP nuclear localization and αSMA expression, while inhibition of YAP attenuates αSMA expression. Overall, our findings indicate that a G9a‐LATS‐YAP signaling cascade regulates mammary epithelial cell response to matrix stiffness and TGFβ1. |
| format | Article |
| id | doaj-art-cd739c01b1c44f1aaca0b82d13f6227e |
| institution | Matheson Library |
| issn | 2573-9832 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | FASEB BioAdvances |
| spelling | doaj-art-cd739c01b1c44f1aaca0b82d13f6227e2025-07-26T08:54:37ZengWileyFASEB BioAdvances2573-98322025-07-0177n/an/a10.1096/fba.2025-00117Matrix Stiffness Regulates TGFβ1‐Induced αSMA Expression via a G9a‐LATS‐YAP Signaling CascadeChinmay S. Sankhe0Jessica L. Sacco1Victoria L. Crunkleton2Malcom Díaz García3Matthew J. Bierowski4David Vidotto Rezende Soares5Jacob A. Karnick6Rachel L. Cecco7Arefeh Abbasi8Joy Kirigo9Thomas K. Wood10Esther W. Gomez11Department of Chemical Engineering Pennsylvania State University University Park Pennsylvania USADepartment of Chemical Engineering Pennsylvania State University University Park Pennsylvania USADepartment of Materials Science and Engineering North Carolina State University Raleigh North Carolina USADepartment of Mechanical Engineering University of Puerto Rico Mayagüez Puerto Rico USADepartment of Chemical Engineering Pennsylvania State University University Park Pennsylvania USADepartment of Chemical Engineering Pennsylvania State University University Park Pennsylvania USADepartment of Chemical Engineering Pennsylvania State University University Park Pennsylvania USADepartment of Chemical Engineering Pennsylvania State University University Park Pennsylvania USADepartment of Chemical Engineering Pennsylvania State University University Park Pennsylvania USADepartment of Chemical Engineering Pennsylvania State University University Park Pennsylvania USADepartment of Chemical Engineering Pennsylvania State University University Park Pennsylvania USADepartment of Chemical Engineering Pennsylvania State University University Park Pennsylvania USAABSTRACT Extracellular matrix stiffness is enhanced in cancer and fibrosis; however, there is limited knowledge on how matrix mechanics modulate expression and signaling of the methyltransferase G9a. Here, we show that matrix stiffness and transforming growth factor (TGF)‐β1 signaling together regulate G9a expression and the levels of the histone mark H3K9me2. Suppressing the activity and expression of G9a attenuates TGFβ1‐induced alpha smooth muscle actin (αSMA) and N‐cadherin expression and cell morphology changes in mammary epithelial cells cultured on stiff substrata. Knockdown of G9a increases the expression of large tumor suppressor kinase 2 (LATS2) and decreases the nuclear localization of yes associated protein (YAP). Furthermore, inhibition of LATS promotes an increase in YAP nuclear localization and αSMA expression, while inhibition of YAP attenuates αSMA expression. Overall, our findings indicate that a G9a‐LATS‐YAP signaling cascade regulates mammary epithelial cell response to matrix stiffness and TGFβ1.https://doi.org/10.1096/fba.2025-00117epigenomicsepithelial cellsextracellular matrixhistone methyltransferaseshydrogelsmammary gland |
| spellingShingle | Chinmay S. Sankhe Jessica L. Sacco Victoria L. Crunkleton Malcom Díaz García Matthew J. Bierowski David Vidotto Rezende Soares Jacob A. Karnick Rachel L. Cecco Arefeh Abbasi Joy Kirigo Thomas K. Wood Esther W. Gomez Matrix Stiffness Regulates TGFβ1‐Induced αSMA Expression via a G9a‐LATS‐YAP Signaling Cascade FASEB BioAdvances epigenomics epithelial cells extracellular matrix histone methyltransferases hydrogels mammary gland |
| title | Matrix Stiffness Regulates TGFβ1‐Induced αSMA Expression via a G9a‐LATS‐YAP Signaling Cascade |
| title_full | Matrix Stiffness Regulates TGFβ1‐Induced αSMA Expression via a G9a‐LATS‐YAP Signaling Cascade |
| title_fullStr | Matrix Stiffness Regulates TGFβ1‐Induced αSMA Expression via a G9a‐LATS‐YAP Signaling Cascade |
| title_full_unstemmed | Matrix Stiffness Regulates TGFβ1‐Induced αSMA Expression via a G9a‐LATS‐YAP Signaling Cascade |
| title_short | Matrix Stiffness Regulates TGFβ1‐Induced αSMA Expression via a G9a‐LATS‐YAP Signaling Cascade |
| title_sort | matrix stiffness regulates tgfβ1 induced αsma expression via a g9a lats yap signaling cascade |
| topic | epigenomics epithelial cells extracellular matrix histone methyltransferases hydrogels mammary gland |
| url | https://doi.org/10.1096/fba.2025-00117 |
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