RGD Reference Report - Epigenetic silencing of Aristaless-like homeobox-4, a potential tumor suppressor gene associated with lung cancer. - Rat Genome Database

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Epigenetic silencing of Aristaless-like homeobox-4, a potential tumor suppressor gene associated with lung cancer.

Authors: Liu, Wen-Bin  Han, Fei  Du, Xing-Hua  Jiang, Xiao  Li, Yong-Hong  Liu, Yong  Chen, Hong-Qiang  Ao, Lin  Cui, Zhi-Hong  Cao, Jia  Liu, Jin-Yi 
Citation: Liu WB, etal., Int J Cancer. 2014 Mar 15;134(6):1311-22. doi: 10.1002/ijc.28472. Epub 2013 Nov 11.
RGD ID: 153344522
Pubmed: PMID:24037716   (View Abstract at PubMed)
DOI: DOI:10.1002/ijc.28472   (Journal Full-text)

Using genome-wide methylation screening, we found Aristaless-like homeobox-4 (ALX4) preferentially methylated in lung cancer. ALX4 is a putative transcription factor that belongs to the family of paired-class homeoproteins involved in epithelial development. However, the role of ALX4 in tumorigenesis remains largely unclear. Here, we analyzed its epigenetic regulation, biological functions and related molecular mechanisms in lung cancer. CpG island methylation and expression of ALX4 were evaluated by methylation-specific polymerase chain reaction (PCR), bisulfite genomic sequencing, reverse-transcription PCR and Western blotting. ALX4 functions were determined by cell viability, colony formation, flow cytometry and in vivo tumorigenicity assays. ALX4 hypermethylation was detected in 55% (54/98) of primary lung cancers compared to none (0/20) of the normal lung tissue samples tested (p < 0.01). ALX4 was readily expressed in normal lung tissues with an unmethylated status, but downregulated or silenced in 90% (9/10) of lung cancer cell lines with a hypermethylation status. Demethylation experiments further confirmed that loss of ALX4 expression was regulated by CpG island hypermethylation. Re-expression of ALX4 in lung cancer cell lines suppressed cell viability, colony formation and migration, whereas it induced apoptosis and G1/S arrest and restrained the tumorigenicity in nude mice. These effects were associated with upregulation of proapoptotic proteins caspase-7, -8 and -9, and downregulation of Bcl-2. On the other hand, knockdown of ALX4 expression by siRNA increased cell viability and proliferation, whereas it inhibited apoptosis and cell cycle arrest. In conclusion, our results suggest that ALX4 is a novel putative tumor suppressor with epigenetic silencing in lung carcinogenesis.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
ALX4Humanbronchiolo-alveolar adenocarcinoma amelioratesIMP  RGD 
Alx4Ratbronchiolo-alveolar adenocarcinoma amelioratesISOALX4 (Homo sapiens) RGD 
Alx4Mousebronchiolo-alveolar adenocarcinoma amelioratesISOALX4 (Homo sapiens) RGD 
ALX4Humanlung cancer  IDA DNA:hypermethylation:CpG_island: RGD 
Alx4Ratlung cancer  ISOALX4 (Homo sapiens)DNA:hypermethylation:CpG_island: RGD 
Alx4Mouselung cancer  ISOALX4 (Homo sapiens)DNA:hypermethylation:CpG_island: RGD 

Objects Annotated

Genes (Rattus norvegicus)
Alx4  (ALX homeobox 4)

Genes (Mus musculus)
Alx4  (aristaless-like homeobox 4)

Genes (Homo sapiens)
ALX4  (ALX homeobox 4)


Additional Information