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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Immunological Tolerance and Regulation
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1430187
This article is part of the Research Topic Deciphering the Intricate Relationship between Epigenetics and Transcription in Immune System Regulation View all articles

TGF-β and TNF-α interaction promotes the expression of MMP-9 through H3K36 dimethylation: Implications in Breast Cancer Metastasis

Provisionally accepted
Shihab Kochumon Shihab Kochumon 1Amnah Al-Sayyar Amnah Al-Sayyar 2Texy Jacob Texy Jacob 1Dr. Fatemah Bahman Dr. Fatemah Bahman 1Nadeem Akhter Nadeem Akhter 1Ajit Wilson Ajit Wilson 1Sardar Sindhu Sardar Sindhu 1Yusuf A. Hannun Yusuf A. Hannun 3Rasheed Ahmad Rasheed Ahmad 1*Fahd Al Mulla Fahd Al Mulla 1*
  • 1 Dasman Diabetes Institute, Kuwait City, Kuwait
  • 2 INSERM U1104 Centre d'immunologie de Marseille-Luminy (CIML), Marseille, Provence-Alpes-Côte d'Azur, France
  • 3 Cancer Center, Stony Brook Medicine, Stony Brook, New York, United States

The final, formatted version of the article will be published soon.

    Increased MMP-9 expression in the tumor microenvironment (TME) plays a crucial role in the extracellular matrix remodeling to facilitate cancer invasion and metastasis. However, the mechanism of MMP-9 upregulation in TME remains elusive. Since TGF-β and TNF-α levels are elevated in TE, we asked whether these two agents interacted to induce/augment MMP-9 expression. Using a wellestablished MDA-MB-231 breast cancer model, we found that the synergy between TGF-β and TNFα led to MMP-9 upregulation at the transcriptional and translational levels, compared to treatments with each agent alone. Our in vitro findings are corroborated by co-expression of elevated MMP-9 with TGF-β and TNF-α in human breast cancer tissues. Mechanistically, we found that the MMP-9 upregulation driven by TGF-β/TNF-α cooperativity was attenuated by selective inhibition of the TGF-βRI/Smad3 pathway. Comparable outcomes were observed upon inhibition of TGF-β-induced phosphorylation of Smad2/3 and p38. As expected, the cells defective in Smad2/3 or p38-mediated signaling did not exhibit this synergistic induction of MMP-9. Importantly, the inhibition of histone methylation but not acetylation dampened the synergistic MMP-9 expression. Histone modification profiling further identified the H3K36me2 as an epigenetic regulatory mark of this synergy. Moreover, TGF-β/TNF-α co-stimulation led to increased levels of the transcriptionally permissive dimethylation mark at H3K36 in the MMP-9 promoter. Comparable outcomes were noted in cells deficient in NSD2 histone methyltransferase. In conclusion, our findings support a cooperativity model in which TGF-β could amplify the TNF-α-mediated MMP-9 production via chromatin remodeling and facilitate breast cancer invasion and metastasis.

    Keywords: Histone Methylation, H3K36me2, MMP-9, Smad2/3, TNF-α, TGF-β

    Received: 09 May 2024; Accepted: 26 Jul 2024.

    Copyright: © 2024 Kochumon, Al-Sayyar, Jacob, Bahman, Akhter, Wilson, Sindhu, Hannun, Ahmad and Al Mulla. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Rasheed Ahmad, Dasman Diabetes Institute, Kuwait City, Kuwait
    Fahd Al Mulla, Dasman Diabetes Institute, Kuwait City, Kuwait

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