MUC1-C intersects chronic inflammation with epigenetic reprogramming by regulating the set1a compass complex in cancer progression
Abstract Chronic inflammation promotes epigenetic reprogramming in cancer progression by pathways that remain unclear. The oncogenic MUC1-C protein is activated by the inflammatory NF-κB pathway in cancer cells. There is no known involvement of MUC1-C in regulation of the COMPASS family of H3K4 meth...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-10-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-023-05395-9 |
| _version_ | 1827708958283923456 |
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| author | Atrayee Bhattacharya Atsushi Fushimi Keyi Wang Nami Yamashita Yoshihiro Morimoto Satoshi Ishikawa Tatsuaki Daimon Tao Liu Song Liu Mark D. Long Donald Kufe |
| author_facet | Atrayee Bhattacharya Atsushi Fushimi Keyi Wang Nami Yamashita Yoshihiro Morimoto Satoshi Ishikawa Tatsuaki Daimon Tao Liu Song Liu Mark D. Long Donald Kufe |
| author_sort | Atrayee Bhattacharya |
| collection | DOAJ |
| description | Abstract Chronic inflammation promotes epigenetic reprogramming in cancer progression by pathways that remain unclear. The oncogenic MUC1-C protein is activated by the inflammatory NF-κB pathway in cancer cells. There is no known involvement of MUC1-C in regulation of the COMPASS family of H3K4 methyltransferases. We find that MUC1-C regulates (i) bulk H3K4 methylation levels, and (ii) the COMPASS SET1A/SETD1A and WDR5 genes by an NF-κB-mediated mechanism. The importance of MUC1-C in regulating the SET1A COMPASS complex is supported by the demonstration that MUC1-C and WDR5 drive expression of FOS, ATF3 and other AP-1 family members. In a feedforward loop, MUC1-C, WDR5 and AP-1 contribute to activation of genes encoding TRAF1, RELB and other effectors in the chronic NF-κB inflammatory response. We also show that MUC1-C, NF-κB, WDR5 and AP-1 are necessary for expression of the (i) KLF4 master regulator of the pluripotency network and (ii) NOTCH1 effector of stemness. In this way, MUC1-C/NF-κB complexes recruit SET1A/WDR5 and AP-1 to enhancer-like signatures in the KLF4 and NOTCH1 genes with increases in H3K4me3 levels, chromatin accessibility and transcription. These findings indicate that MUC1-C regulates the SET1A COMPASS complex and the induction of genes that integrate NF-κB-mediated chronic inflammation with cancer progression. |
| first_indexed | 2024-03-10T17:13:08Z |
| format | Article |
| id | doaj.art-5d8039b4e2e841e5972c3d38760a04a4 |
| institution | Directory Open Access Journal |
| issn | 2399-3642 |
| language | English |
| last_indexed | 2024-03-10T17:13:08Z |
| publishDate | 2023-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj.art-5d8039b4e2e841e5972c3d38760a04a42023-11-20T10:34:38ZengNature PortfolioCommunications Biology2399-36422023-10-016111510.1038/s42003-023-05395-9MUC1-C intersects chronic inflammation with epigenetic reprogramming by regulating the set1a compass complex in cancer progressionAtrayee Bhattacharya0Atsushi Fushimi1Keyi Wang2Nami Yamashita3Yoshihiro Morimoto4Satoshi Ishikawa5Tatsuaki Daimon6Tao Liu7Song Liu8Mark D. Long9Donald Kufe10Dana-Farber Cancer Institute, Harvard Medical SchoolDana-Farber Cancer Institute, Harvard Medical SchoolDana-Farber Cancer Institute, Harvard Medical SchoolDana-Farber Cancer Institute, Harvard Medical SchoolDana-Farber Cancer Institute, Harvard Medical SchoolDana-Farber Cancer Institute, Harvard Medical SchoolDana-Farber Cancer Institute, Harvard Medical SchoolDepartment of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer CenterDepartment of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer CenterDepartment of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer CenterDana-Farber Cancer Institute, Harvard Medical SchoolAbstract Chronic inflammation promotes epigenetic reprogramming in cancer progression by pathways that remain unclear. The oncogenic MUC1-C protein is activated by the inflammatory NF-κB pathway in cancer cells. There is no known involvement of MUC1-C in regulation of the COMPASS family of H3K4 methyltransferases. We find that MUC1-C regulates (i) bulk H3K4 methylation levels, and (ii) the COMPASS SET1A/SETD1A and WDR5 genes by an NF-κB-mediated mechanism. The importance of MUC1-C in regulating the SET1A COMPASS complex is supported by the demonstration that MUC1-C and WDR5 drive expression of FOS, ATF3 and other AP-1 family members. In a feedforward loop, MUC1-C, WDR5 and AP-1 contribute to activation of genes encoding TRAF1, RELB and other effectors in the chronic NF-κB inflammatory response. We also show that MUC1-C, NF-κB, WDR5 and AP-1 are necessary for expression of the (i) KLF4 master regulator of the pluripotency network and (ii) NOTCH1 effector of stemness. In this way, MUC1-C/NF-κB complexes recruit SET1A/WDR5 and AP-1 to enhancer-like signatures in the KLF4 and NOTCH1 genes with increases in H3K4me3 levels, chromatin accessibility and transcription. These findings indicate that MUC1-C regulates the SET1A COMPASS complex and the induction of genes that integrate NF-κB-mediated chronic inflammation with cancer progression.https://doi.org/10.1038/s42003-023-05395-9 |
| spellingShingle | Atrayee Bhattacharya Atsushi Fushimi Keyi Wang Nami Yamashita Yoshihiro Morimoto Satoshi Ishikawa Tatsuaki Daimon Tao Liu Song Liu Mark D. Long Donald Kufe MUC1-C intersects chronic inflammation with epigenetic reprogramming by regulating the set1a compass complex in cancer progression Communications Biology |
| title | MUC1-C intersects chronic inflammation with epigenetic reprogramming by regulating the set1a compass complex in cancer progression |
| title_full | MUC1-C intersects chronic inflammation with epigenetic reprogramming by regulating the set1a compass complex in cancer progression |
| title_fullStr | MUC1-C intersects chronic inflammation with epigenetic reprogramming by regulating the set1a compass complex in cancer progression |
| title_full_unstemmed | MUC1-C intersects chronic inflammation with epigenetic reprogramming by regulating the set1a compass complex in cancer progression |
| title_short | MUC1-C intersects chronic inflammation with epigenetic reprogramming by regulating the set1a compass complex in cancer progression |
| title_sort | muc1 c intersects chronic inflammation with epigenetic reprogramming by regulating the set1a compass complex in cancer progression |
| url | https://doi.org/10.1038/s42003-023-05395-9 |
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