The long noncoding RNA lncZic2 drives the self-renewal of liver tumor-initiating cells via the protein kinase C substrates MARCKS and MARCKSL1.
Liver tumor-initiating cells (TICs) form small subsets of cells in hepatocellular tumors and account for tumorigenesis, metastasis, recurrence, and drug resistance. Recently, we found that the transcription factor Zic family member 2 (ZIC2) is highly expressed in liver TICs and required for their self-renewal. However, the molecular mechanisms underlying self-renewal of liver TICs remain unclear. Here, using expression profiling and CRISPR-interference assays with clinical samples of human liver cancers, we identified a long noncoding RNA (lncRNA), lncZic2, that is located near the ZIC2 locus and was highly expressed in liver cancer and liver TICs. We found that lncZic2 is required for the self-renewal of liver TICs in a ZIC2-independent manner. lncZic2 drove the expression of myristoylated alanine-rich protein kinase C substrate (MARCKS) and MARCKS-like 1 (MARCKSL1), whose expression levels were increased during liver tumorigenesis and liver TIC self-renewal. Mechanistically, lncZic2 interacted with BRM/SWI2-related gene 1 (BRG1) and recruited this transcriptional regulator to the promoters of the MARCKS and MARCKSL1 gene, which activated expression of these genes. Moreover, we noted that depletion of lncZic2 and BRG1 decreases MARCKS and MARCKSL1 expression and diminishes liver TIC levels. In conclusion, lncZic2 is required for the self-renewal of liver TICs by up-regulating MARCKS and MARCKSL1 gene expression via the transcription factor BRG1. Our findings suggest that the lncZic2-BRG1-MARCKS/MARCKSL1 signaling cascade might be a potential target for eliminating liver TICs in the management of liver cancer.
['Chen|Zhenzhen|Z|', 'Liu|Yating|Y|', 'Yao|Lintong|L|', 'Guo|Shiying|S|', 'Gao|Yanfeng|Y|', 'Zhu|Pingping|P|']
D002148:Calmodulin-Binding Proteins D006528:Carcinoma, Hepatocellular D049109:Cell Proliferation D002471:Cell Transformation, Neoplastic D006801:Humans D008113:Liver Neoplasms D008565:Membrane Proteins D008840:Microfilament Proteins D000076250:Myristoylated Alanine-Rich C Kinase Substrate D014411:Neoplastic Stem Cells D009687:Nuclear Proteins D011401:Promoter Regions, Genetic D011493:Protein Kinase C D062085:RNA, Long Noncoding D015398:Signal Transduction D014157:Transcription Factors D014407:Tumor Cells, Cultured
self-renewal Zic family member 2 liver cancer myristoylated alanine-rich protein kinase C substrate cancer stem cells chromatin regulation long noncoding RNA (long ncRNA, lncRNA) protein kinase C signaling tumor promoter tumor targeting tumor therapy