HMGA1 promotes the tumorigenesis of colorectal cancer by increasing lipid synthesis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1040882 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26842713_1.fastq.gz | Fastqsanger.gz | |||
| SRR26842713_2.fastq.gz | Fastqsanger.gz | |||
| SRR26842714_1.fastq.gz | Fastqsanger.gz | |||
| SRR26842714_2.fastq.gz | Fastqsanger.gz | |||
| SRR26842715_1.fastq.gz | Fastqsanger.gz |
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Project description:Metabolic reprogramming is a typical feature of tumors, in which biological macromolecules and energy produced in abnormal metabolism meet the requirements of highly proliferative tumor cells and participate in multiple stages of tumor development. High mobility group A1 (HMGA1) is a structural transcription factor, which plays a carcinogenic role in regulating the transcription of oncogenes. Bioinformatics analysis showed that HMGA1 was overexpressed in human CRC. However, the mechanisms by which HMGA1 promotes the tumorigenesis of CRC remains unknown. Herein, we applied intestinal epithelium conditional knockout (Hmga1△IEC) and knock-in (Hmga1IEC-OE/+) mice of HMGA1 to induce CRC, and identified that HMGA1 promotes colorectal cancer growth by increasing lipid synthesis. Single-cell sequencing (scRNA seq) and immunohistochemical staining showed that HMGA1 was highly expressed in the epithelial cells of CRC. HMGA1 promoted the CRC cell proliferation and accelerated CRC development in HMGA1-knock-in (Hmga1IEC-OE/+) mice. Knockout of HMGA1 (Hmga1△IEC) in intestinal epithelial cells of mice reduced the lipid accumulation and inhibited the occurrence and development of CRC. We further characterized that HMGA1 upregulated the level of fatty acid synthase (FASN) through enhancing the transcriptional binding of sterol regulatory element-binding protein 1 (SREBP1) to the promoter of FASN, leading to an increase in lipid synthesis in intestinal epithelial cells. High fat diet (HFD) aggravated the malignant progression of CRC in Hmga1△IEC mice and reversed the inhibitory effect of HMGA1 depletion on CRC. Administration Orlistat (50 mg/kg), an inhibitor of FASN-mediated lipid synthesis, into Hmga1-knock-in (Hmga1IEC-OE/+) mice markedly reduced lipid accumulation in intestinal epithelial cells and decreased the tumorigenesis of CRC. Taken together, our data suggest that HMGA1 promotes the tumorigenesis of colorectal cancer by up-regulating FASN-mediated de novo fatty acid synthesis. Our findings provide strong evidence supporting therapeutic intervention of lipid accumulation for the prevention and treatment of CRC
2024-10-10 | GSE247894 | GEO
Project description:Mutated cells undergo changes in chromatin accessibility and gene expression, resulting in aberrant proliferation and differentiation, although how this occurs is unclear. HMGA1 chromatin regulators are abundant in stem cells and oncogenic in diverse tissues; however, their role in colon tumorigenesis is only beginning to emerge. Here, we uncover a previously unknown epigenetic program whereby HMGA1 amplifies Wnt signaling during colon tumorigenesis driven by inflammatory microbiota and/or Adenomatous polyposis coli (Apc) inactivation. Mechanistically, HMGA1 “opens” chromatin to up-regulate the stem cell regulator, Ascl2, and downstream Wnt effectors, promoting stem and Paneth-like cell states while depleting differentiated enterocytes. Loss of just one Hmga1 allele within colon epithelium restrains tumorigenesis and Wnt signaling driven by mutant Apc and inflammatory microbiota. However, HMGA1 deficiency has minimal effects in colon epithelium under homeostatic conditions. In human colon cancer cells, HMGA1 directly induces ASCL2 by recruiting activating histone marks. Silencing HMGA1 disrupts oncogenic properties, whereas re-expression of ASCL2 partially rescues these phenotypes. Further, HMGA1 and ASCL2 are co-expressed and up-regulated in human colorectal cancer. Together, our results establish HMGA1 as an epigenetic gatekeeper of Wnt signals and cell state under conditions of APC inactivation, illuminating HMGA1 as a potential therapeutic target in colon cancer.
2025-02-05 | GSE278871 | GEO
Project description:Mutated cells undergo changes in chromatin accessibility and gene expression, resulting in aberrant proliferation and differentiation, although how this occurs is unclear. HMGA1 chromatin regulators are abundant in stem cells and oncogenic in diverse tissues; however, their role in colon tumorigenesis is only beginning to emerge. Here, we uncover a previously unknown epigenetic program whereby HMGA1 amplifies Wnt signaling during colon tumorigenesis driven by inflammatory microbiota and/or Adenomatous polyposis coli (Apc) inactivation. Mechanistically, HMGA1 “opens” chromatin to up-regulate the stem cell regulator, Ascl2, and downstream Wnt effectors, promoting stem and Paneth-like cell states while depleting differentiated enterocytes. Loss of just one Hmga1 allele within colon epithelium restrains tumorigenesis and Wnt signaling driven by mutant Apc and inflammatory microbiota. However, HMGA1 deficiency has minimal effects in colon epithelium under homeostatic conditions. In human colon cancer cells, HMGA1 directly induces ASCL2 by recruiting activating histone marks. Silencing HMGA1 disrupts oncogenic properties, whereas re-expression of ASCL2 partially rescues these phenotypes. Further, HMGA1 and ASCL2 are co-expressed and up-regulated in human colorectal cancer. Together, our results establish HMGA1 as an epigenetic gatekeeper of Wnt signals and cell state under conditions of APC inactivation, illuminating HMGA1 as a potential therapeutic target in colon cancer.
2025-02-05 | GSE279070 | GEO
Project description:Metabolic reprogramming is a hallmark of cancer, enabling tumor cells to meet the high energy and biosynthetic demands required for their proliferation. High mobility group A1 (HMGA1) is a structural transcription factor and frequently overexpressed in human colorectal cancer (CRC). Here, we show that HMGA1 promotes CRC progression by driving lipid synthesis in a AOM/DSS-induced CRC mouse model. Using conditional knockout (Hmga1△IEC) and knock-in (Hmga1IEC-OE/+) mouse models, we demonstrate that HMGA1 enhances CRC cell proliferation and accelerates tumor development by upregulating fatty acid synthase (FASN). Mechanistically, HMGA1 increases the transcriptional activity of sterol regulatory element-binding protein 1 (SREBP1) on the FASN promoter, leading to increased lipid accumulation in intestinal epithelial cells. Moreover, a high-fat diet exacerbates CRC progression in Hmga1△IEC mice, while pharmacological inhibition of FASN by orlistat reduces tumor growth in Hmga1IEC-OE/+ mice. Our findings suggest that targeting lipid metabolism could offer a promising therapeutic strategy for CRC.
| S-EPMC11568219 | biostudies-literature
Project description:Myeloproliferative neoplasms (MPN) transform to myelofibrosis (MF) and highly lethal acute myeloid leukemia (AML), although actionable mechanisms driving progression remain elusive. The HMGA1 chromatin regulator is up-regulated during MPN progression with highest levels after transformation. HMGA1 depletion in JAK2V617F MPN AML cell lines disrupts proliferation, clonogenicity, and leukemic engraftment. Surprisingly, loss of just a single Hmga1 allele prevents progression to MF in JAK2V617F transgenic mice, decreasing blood counts and expansion in stem and myeloid progenitors while preventing splenomegaly and fibrosis within the spleen and bone marrow. RNA sequencing revealed HMGA1-dependent transcriptional networks that govern proliferation (E2F, G2M, mitosis, MYC targets) and cell fate, including the GATA2 master regulatory gene. Silencing GATA2 recapitulates phenotypes observed with HMGA1 depletion whereas GATA2 re-expression partially rescues leukemogenesis. HMGA1 transactivates GATA2 through sequences near the developmental enhancer (+9.5), increasing chromatin accessibility and recruiting active histone marks. Further, HMGA1 transcriptional networks, including GATA2, are activated in human MF after leukemic transformation. Further, HMGA1 depletion synergizes with the JAK2 inhibitor, ruxolitinib, to prolong survival in murine MPN AML. These findings illuminate HMGA1 as a key epigenetic switch required for MPN transformation and promising therapeutic target to treat or prevent disease progression.
2023-10-05 | GSE197942 | GEO
Project description:Myeloproliferative neoplasms (MPN) transform to myelofibrosis (MF) and highly lethal acute myeloid leukemia (AML), although actionable mechanisms driving progression remain elusive. The HMGA1 chromatin regulator is up-regulated during MPN progression with highest levels after transformation. HMGA1 depletion in JAK2V617F MPN AML cell lines disrupts proliferation, clonogenicity, and leukemic engraftment. Surprisingly, loss of just a single Hmga1 allele prevents progression to MF in JAK2V617F transgenic mice, decreasing blood counts and expansion in stem and myeloid progenitors while preventing splenomegaly and fibrosis within the spleen and bone marrow. RNA sequencing revealed HMGA1-dependent transcriptional networks that govern proliferation (E2F, G2M, mitosis, MYC targets) and cell fate, including the GATA2 master regulatory gene. Silencing GATA2 recapitulates phenotypes observed with HMGA1 depletion whereas GATA2 re-expression partially rescues leukemogenesis. HMGA1 transactivates GATA2 through sequences near the developmental enhancer (+9.5), increasing chromatin accessibility and recruiting active histone marks. Further, HMGA1 transcriptional networks, including GATA2, are activated in human MF after leukemic transformation. Further, HMGA1 depletion synergizes with the JAK2 inhibitor, ruxolitinib, to prolong survival in murine MPN AML. These findings illuminate HMGA1 as a key epigenetic switch required for MPN transformation and promising therapeutic target to treat or prevent disease progression.
2023-10-05 | GSE189569 | GEO
Project description:Myeloproliferative neoplasms (MPN) transform to myelofibrosis (MF) and highly lethal acute myeloid leukemia (AML), although actionable mechanisms driving progression remain elusive. The HMGA1 chromatin regulator is up-regulated during MPN progression with highest levels after transformation. HMGA1 depletion in JAK2V617F MPN AML cell lines disrupts proliferation, clonogenicity, and leukemic engraftment. Surprisingly, loss of just a single Hmga1 allele prevents progression to MF in JAK2V617F transgenic mice, decreasing blood counts and expansion in stem and myeloid progenitors while preventing splenomegaly and fibrosis within the spleen and bone marrow. RNA sequencing revealed HMGA1-dependent transcriptional networks that govern proliferation (E2F, G2M, mitosis, MYC targets) and cell fate, including the GATA2 master regulatory gene. Silencing GATA2 recapitulates phenotypes observed with HMGA1 depletion whereas GATA2 re-expression partially rescues leukemogenesis. HMGA1 transactivates GATA2 through sequences near the developmental enhancer (+9.5), increasing chromatin accessibility and recruiting active histone marks. Further, HMGA1 transcriptional networks, including GATA2, are activated in human MF after leukemic transformation. Further, HMGA1 depletion synergizes with the JAK2 inhibitor, ruxolitinib, to prolong survival in murine MPN AML. These findings illuminate HMGA1 as a key epigenetic switch required for MPN transformation and promising therapeutic target to treat or prevent disease progression.
2023-10-05 | GSE183374 | GEO
Project description:Myeloproliferative neoplasms (MPN) transform to myelofibrosis (MF) and highly lethal acute myeloid leukemia (AML), although actionable mechanisms driving progression remain elusive. The HMGA1 chromatin regulator is up-regulated during MPN progression with highest levels after transformation. HMGA1 depletion in JAK2V617F MPN AML cell lines disrupts proliferation, clonogenicity, and leukemic engraftment. Surprisingly, loss of just a single Hmga1 allele prevents progression to MF in JAK2V617F transgenic mice, decreasing blood counts and expansion in stem and myeloid progenitors while preventing splenomegaly and fibrosis within the spleen and bone marrow. RNA sequencing revealed HMGA1-dependent transcriptional networks that govern proliferation (E2F, G2M, mitosis, MYC targets) and cell fate, including the GATA2 master regulatory gene. Silencing GATA2 recapitulates phenotypes observed with HMGA1 depletion whereas GATA2 re-expression partially rescues leukemogenesis. HMGA1 transactivates GATA2 through sequences near the developmental enhancer (+9.5), increasing chromatin accessibility and recruiting active histone marks. Further, HMGA1 transcriptional networks, including GATA2, are activated in human MF after leukemic transformation. Further, HMGA1 depletion synergizes with the JAK2 inhibitor, ruxolitinib, to prolong survival in murine MPN AML. These findings illuminate HMGA1 as a key epigenetic switch required for MPN transformation and promising therapeutic target to treat or prevent disease progression.
2023-10-05 | GSE189568 | GEO
Project description:Enhanced fatty acid synthesis provides proliferation and survival advantages for tumor cells. Apelin is an adipokine, which serves as a ligand of G protein-coupled receptors that promote tumor growth in malignant cancers. Here, we confirmed that apelin increased sterol regulatory element-binding protein 1 (SREBP1) activity and induced the expression of glutamine amidotransferase for deamidating high-mobility group A 1 (HMGA1) to promote fatty acid synthesis and proliferation of lung cancer cells. This post-translational modification stabilized the HMGA1 expression and enhanced the formation of the apelin-HMGA1-SREBP1 complex to facilitate SREBP1 activity for lipid metabolism and lung cancer cell growth. We uncovered the pivotal role of apelin-mediated deamidation of HMGA1 in lipid metabolism and tumorigenesis of lung cancer cells.
| S-EPMC9633285 | biostudies-literature
Project description:Analysis of MDA-MB-231 breast cancer cells depleted for High Mobility Group A1 (HMGA1) using siRNA. HMGA1 is involved in invasion and metastasis in breast cancer cells. Results identify the specific transcriptional program induced by HMGA1 in highly metastatic breast cancer cells. MDA-MB-231 cells were transfected with HMGA1-specific siRNA or a control siRNA. Transfections were performed by using Lipofectamin RNAiMAX (Invitrogen) according to the manufacturer's procedure. Seventy-two hours after transfection, samples were processed for total RNA extraction and hybridization on Affymetrix microarrays. Four biological replicas (A, B, C, D) were used for each of the two conditions, for a total of 8 samples.
2013-12-10 | E-GEOD-35525 | biostudies-arrayexpress