KAT6A acetylation of SMAD3 regulates tumor metastasis in triple-negative breast cancer
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ABSTRACT:
PROVIDER: PRJNA718834 | ENA |
REPOSITORIES: ENA
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Project description:Aberrant SMAD3 activation has been implicated as a driving event in cancer metastasis. However, the drivers of SMAD3 activation are poorly defined. Here, we identify SMAD3 as a non-histone substrate of lysine acetyltransferase 6A (KAT6A). The acetylation of SMAD3 at K20 and K117 by KAT6A with promotes SMAD3 association with oncogenic H3K23ac reader TRIM24 and upregulation of immune response-related cytokines. This event in turn leads to enhanced myeloid-derived suppressor cell (MDSC) recruitment and triple-negative breast cancer (TNBC) metastasis. Inhibiting KAT6A in combination with anti-PD-L1 therapy in treating breast cancer xenograft-bearing animals markedly attenuates TNBC metastasis and provides a significant survival benefit. Thus, our work presents an KAT6A acetylation-dependent regulatory mechanism governing SMAD3 oncogenic function and provides insight into how targeting an epigenetic factor with immunotherapies enhances the anti-metastasis efficacy.
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Project description:The testis protein ZNF165 is aberrantly expressed in triple-negative breast cancer (TNBC), where it modulates TGFβ signaling to promote tumor growth and survival. To investigate whether ZNF165 functions in this capacity via cooperation with SMAD3, a canonical TGFβ-induced transcription factor, we performed ChIP-seq for both factors in TNBC cell lines (WHIM12 and SUM159). Additionally, we established genomic binding profiles for ZNF446, a previously uncharacterized transcription factor that we have identified as a member of a ZNF165-SMAD3 complex.
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Project description:The lysine acetyltransferase KAT6A (MOZ, MYST3) belongs to the MYST family of chromatin regulators, facilitating histone acetylation. Dysregulation of KAT6A has been implicated in developmental syndromes and the onset of acute myeloid leukemia (AML). Previous work suggests that KAT6A is recruited to its genomic targets by a combinatorial function of histone binding PHD fingers, transcription factors and chromatin binding interaction partners. Here, we demonstrated that a winged helix domain at the N-terminus of KAT6A specifically interacts with unmethylated CpG motifs. This DNA binding function leads to the association of KAT6A to unmethylated CpG islands (CGIs) genome wide. Mutation of the essential amino acids completely abrogates the enrichment of KAT6A at CGIs. Overexpression of a KAT6A WH1 mutant has a dominant negative effect on H3K9 histone acetylation, which is comparable to the effects upon overexpression of a KAT6A HAT domain mutant. Taken together, our work revealed a previously unrecognized chromatin recruitment mechanism of KAT6A, offering a new perspective on the role of KAT6A in gene regulation and human diseases
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Project description:Acetylation of histones by lysine acetyltransferases (KATs) is essential for transcriptional regulation of gene expression. The MYST family of KATs (KAT5-8) includes the oncogenes KAT6A (MOZ) and KAT6B (MORF/QKF). KAT6A has key roles in promoting cell proliferation through transcriptional activation of negative regulators of the Cdkn2a locus, which encode the tumor suppressors INK4A and ARF. To examine the loss of KAT6A function, mouse embryonic fibroblasts (MEFs) were isolated from E13.5 Kat6a+/+ and Kat6a–/– embryos and RNA-seq profiling was performed.
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Project description:The lysine acetyltransferase KAT6A (MOZ, MYST3) belongs to the MYST family of chromatin regulators, facilitating histone acetylation. Dysregulation of KAT6A has been implicated in developmental syndromes and the onset of acute myeloid leukemia (AML). Previous work suggests that KAT6A is recruited to its genomic targets by a combinatorial function of histone binding PHD fingers, transcription factors and chromatin binding interaction partners. Here, we demonstrate that a winged helix (WH) domain at the very N-terminus of KAT6A specifically interacts with unmethylated CpG motifs. This DNA binding function leads to the association of KAT6A with unmethylated CpG islands (CGIs) genome-wide. Mutation of the essential amino acids for DNA binding completely abrogates the enrichment of KAT6A at CGIs. In contrast, deletion of a second WH domain or the histone tail binding PHD fingers only subtly influences the binding of KAT6A to CGIs. Overexpression of a KAT6A WH1 mutant has a dominant negative effect on H3K9 histone acetylation, which is comparable to the effects upon overexpression of a KAT6A HAT domain mutant. Taken together, our work revealed a previously unrecognized chromatin recruitment mechanism of KAT6A, offering a new perspective on the role of KAT6A in gene regulation and human diseases.
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Project description:The lysine acetyltransferase KAT6A (MOZ, MYST3) belongs to the MYST family of chromatin regulators, facilitating histone acetylation. Dysregulation of KAT6A has been implicated in developmental syndromes and the onset of acute myeloid leukemia (AML). Previous work suggests that KAT6A is recruited to its genomic targets by a combinatorial function of histone binding PHD fingers, transcription factors and chromatin binding interaction partners. Here, we demonstrate that a winged helix (WH) domain at the very N-terminus of KAT6A specifically interacts with unmethylated CpG motifs. This DNA binding function leads to the association of KAT6A with unmethylated CpG islands (CGIs) genome-wide. Mutation of the essential amino acids for DNA binding completely abrogates the enrichment of KAT6A at CGIs. In contrast, deletion of a second WH domain or the histone tail binding PHD fingers only subtly influences the binding of KAT6A to CGIs. Overexpression of a KAT6A WH1 mutant has a dominant negative effect on H3K9 histone acetylation, which is comparable to the effects upon overexpression of a KAT6A HAT domain mutant. Taken together, our work revealed a previously unrecognized chromatin recruitment mechanism of KAT6A, offering a new perspective on the role of KAT6A in gene regulation and human diseases.
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Project description:RNA N6-methyladenosine (m6A) modification and its regulators fine tune gene expression and contribute to tumorigenesis. Here, we uncover the oncogenic role and mechanism of YTHDC1, an m6A reader positively correlated to poor prognosis in breast cancer patients. In a mammary fat pad mouse model, YTHDC1 significantly promoted lung metastasis of triple negative breast cancer (TNBC) cells. Using transcriptome-wide sequencing techniques, we found dysregulation of metastasis-related pathways following YTHDC1 depletion and demonstrated that YTHDC1 is critical for nuclear export of SMAD3 mRNA. YTHDC1 depletion desensitizes TNBC cells to TGF-β, resulting in impaired TGF-β-induced gene signature and inhibition on epithelial-mesenchymal transition (EMT) and cell migration/invasion, which could be at least partially restored by SMAD3 overexpression. Furthermore, we show that the ability of YTHDC1 to recognize m6A on SMAD3 RNA is important for its oncogenic role. Collectively, our study unravels YTHDC1 as vital for distant TNBC metastasis by promoting TGF-β-mediated EMT via SMAD3.
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Project description:RNA N6-methyladenosine (m6A) modification and its regulators fine tune gene expression and contribute to tumorigenesis. Here, we uncover the oncogenic role and mechanism of YTHDC1, an m6A reader positively correlated to poor prognosis in breast cancer patients. In a mammary fat pad mouse model, YTHDC1 significantly promoted lung metastasis of triple negative breast cancer (TNBC) cells. Using transcriptome-wide sequencing techniques, we found dysregulation of metastasis-related pathways following YTHDC1 depletion and demonstrated that YTHDC1 is critical for nuclear export of SMAD3 mRNA. YTHDC1 depletion desensitizes TNBC cells to TGF-β, resulting in impaired TGF-β-induced gene signature and inhibition on epithelial-mesenchymal transition (EMT) and cell migration/invasion, which could be at least partially restored by SMAD3 overexpression. Furthermore, we show that the ability of YTHDC1 to recognize m6A on SMAD3 RNA is important for its oncogenic role. Collectively, our study unravels YTHDC1 as vital for distant TNBC metastasis by promoting TGF-β-mediated EMT via SMAD3.
2023-03-25 | GSE193155 | GEO
Project description:RNA N6-methyladenosine (m6A) modification and its regulators fine tune gene expression and contribute to tumorigenesis. Here, we uncover the oncogenic role and mechanism of YTHDC1, an m6A reader positively correlated to poor prognosis in breast cancer patients. In a mammary fat pad mouse model, YTHDC1 significantly promoted lung metastasis of triple negative breast cancer (TNBC) cells. Using transcriptome-wide sequencing techniques, we found dysregulation of metastasis-related pathways following YTHDC1 depletion and demonstrated that YTHDC1 is critical for nuclear export of SMAD3 mRNA. YTHDC1 depletion desensitizes TNBC cells to TGF-β, resulting in impaired TGF-β-induced gene signature and inhibition on epithelial-mesenchymal transition (EMT) and cell migration/invasion, which could be at least partially restored by SMAD3 overexpression. Furthermore, we show that the ability of YTHDC1 to recognize m6A on SMAD3 RNA is important for its oncogenic role. Collectively, our study unravels YTHDC1 as vital for distant TNBC metastasis by promoting TGF-β-mediated EMT via SMAD3.
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