Chromatin Remodeling of Colorectal Cancer Liver Metastasis is Mediated by an HGF-PU.1-DPP4 Axis.
Lihua WangErgang WangJorge Prado BalcazarZhenzhen WuKun XiangYi WangQiang HuangMarcos NegreteKai-Yuan ChenWei LiYujie FuAnders DohlmanRobert MinesLiwen ZhangYoshihiko KobayashiTianyi ChenGuizhi ShiJohn Paul ShenScott KopetzPurushothama Rao TataVictor MorenoCharles GersbachGregory CrawfordDavid HsuEmina HuangPengcheng BuXiling ShenPublished in: Advanced science (Weinheim, Baden-Wurttemberg, Germany) (2021)
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/dCas9KRAB or CRISPR/dCas9HDAC 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.
Keyphrases
- genome wide
- dna methylation
- gene expression
- growth factor
- transcription factor
- dna damage
- squamous cell carcinoma
- small cell lung cancer
- copy number
- stem cells
- poor prognosis
- drug induced
- induced apoptosis
- immune response
- histone deacetylase
- papillary thyroid
- deep learning
- cell death
- machine learning
- genome editing
- genome wide identification
- crispr cas
- endoplasmic reticulum stress
- oxidative stress
- human health
- high glucose
- cell cycle arrest
- squamous cell