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Chromatin Remodeling of Colorectal Cancer Liver Metastasis is Mediated by an HGF-PU.1-DPP4 Axis.

ABSTRACT: Colorectal cancer (CRC) metastasizes mainly to the liver, which accounts for the majority of CRC-related deaths. Here it is shown that metastatic cells undergo specific chromatin remodeling in the liver. Hepatic growth factor (HGF) induces phosphorylation of PU.1, a pioneer factor, which in turn binds and opens chromatin regions of downstream effector genes. PU.1 increases histone acetylation at the DPP4 locus. Precise epigenetic silencing by CRISPR/dCas9^KRAB or CRISPR/dCas9^HDAC revealed that individual PU.1-remodeled regulatory elements collectively modulate DPP4 expression and liver metastasis growth. Genetic silencing or pharmacological inhibition of each factor along this chromatin remodeling axis strongly suppressed liver metastasis. Therefore, microenvironment-induced epimutation is an important mechanism for metastatic tumor cells to grow in their new niche. This study presents a potential strategy to target chromatin remodeling in metastatic cancer and the promise of repurposing drugs to treat metastasis.

SUBMITTER: Wang L

PROVIDER: S-EPMC8498885 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Chromatin Remodeling of Colorectal Cancer Liver Metastasis is Mediated by an HGF-PU.1-DPP4 Axis.

Wang Lihua L Wang Ergang E Prado Balcazar Jorge J Wu Zhenzhen Z Xiang Kun K Wang Yi Y Huang Qiang Q Negrete Marcos M Chen Kai-Yuan KY Li Wei W Fu Yujie Y Dohlman Anders A Mines Robert R Zhang Liwen L Kobayashi Yoshihiko Y Chen Tianyi T Shi Guizhi G Shen John Paul JP Kopetz Scott S Tata Purushothama Rao PR Moreno Victor V Gersbach Charles C Crawford Gregory G Hsu David D Huang Emina E Bu Pengcheng P Shen Xiling X

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20210810 19

Colorectal cancer (CRC) metastasizes mainly to the liver, which accounts for the majority of CRC-related deaths. Here it is shown that metastatic cells undergo specific chromatin remodeling in the liver. Hepatic growth factor (HGF) induces phosphorylation of PU.1, a pioneer factor, which in turn binds and opens chromatin regions of downstream effector genes. PU.1 increases histone acetylation at the DPP4 locus. Precise epigenetic silencing by CRISPR/dCas9<sup>KRAB</sup> or CRISPR/dCas9<sup>HDAC< ...[more]

PMID: 34378358

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Project description:BackgroundColorectal cancer (CRC) exhibits a high incidence globally, with the liver being the most common site of distant metastasis. At the time of diagnosis, 20-30% of CRC patients already present with liver metastases. Colorectal liver metastasis (CRLM) is a major cause of mortality among CRC patients. The pathogenesis of CRLM involves complex molecular mechanisms and the hepatic immune microenvironment, but current clinical prevention and treatment are significantly limited. Recent studies have revealed that the major facilitator superfamily domain containing protein-2a (Mfsd2a) plays a pivotal role in the development and metastasis of various cancers. For instance, Mfsd2a inhibits gastric cancer initiation and progression and may impact angiogenesis. However, the mechanisms by which Mfsd2a influences CRC progression and liver metastasis remain unclear.MethodsIn this study, we conducted a survival analysis of Mfsd2a in colorectal cancer using data from the GEPIA and GEO databases, and examined the expression differences between primary tumor (PT) and liver metastasis (LM). We further assessed the clinical significance and prognostic relevance of Mfsd2a through immunohistochemical analysis of tissue samples from 70 CRLM patients. Moreover, Kaplan-Meier analysis was used to perform survival analysis on these patients. The biological function of Mfsd2a in CRLM was confirmed by a series of experiments conducted both in vitro and in vivo. Additionally, we investigated downstream molecular pathways using western blot, Co-immunoprecipitation, immunofluorescence, and mass spectrometry techniques.ResultsWe observed that Mfsd2a expression is reduced in LM compared to PT, and higher Mfsd2a levels are associated with better prognosis in CRLM patients. Furthermore, function assays demonstrated that Mfsd2a suppresses CRC cells proliferation, migration, invasion, and EMT in vitro, while also delaying tumor growth and liver metastasis in vivo. Mechanistically, Mfsd2a interacts with S100A14, enhancing its expression and inhibiting phosphorylation of STAT3. In addition, the STAT3 activator colivelin partially reversed the inhibitory effect of Mfsd2a overexpression on the progression of colorectal cancer and liver metastasis.ConclusionIn summary, Mfsd2a inhibits colorectal cancer progression and liver metastasis by interacting with S100A14, thereby suppressing the phosphorylation of STAT3. Mfsd2a functions as a tumor suppressor in CRLM and could be a promising therapeutic target for treating CRC patients with liver metastasis.

Dataset Information

Chromatin Remodeling of Colorectal Cancer Liver Metastasis is Mediated by an HGF-PU.1-DPP4 Axis.

Publications

Chromatin Remodeling of Colorectal Cancer Liver Metastasis is Mediated by an HGF-PU.1-DPP4 Axis.

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