TAZ expression as a prognostic indicator in colorectal cancer.
The Hippo pathway restricts the activity of transcriptional coactivators TAZ (WWTR1) and YAP. TAZ and YAP are reported to be overexpressed in various cancers, however, their prognostic significance in colorectal cancers remains unstudied. The expression levels of TAZ and YAP, and their downstream transcriptional targets, AXL and CTGF, were extracted from two independent colon cancer patient datasets available in the Gene Expression Omnibus database, totaling 522 patients. We found that mRNA expressions of both TAZ and YAP were positively correlated with those of AXL and CTGF (p<0.05). High level mRNA expression of TAZ, AXL or CTGF significantly correlated with shorter survival. Importantly, patients co-overexpressing all 3 genes had a significantly shorter survival time, and combinatorial expression of these 3 genes was an independent predictor for survival. The downstream target genes for TAZ-AXL-CTGF overexpression were identified by Java application MyStats. Interestingly, genes that are associated with colon cancer progression (ANTXR1, EFEMP2, SULF1, TAGLN, VCAN, ZEB1 and ZEB2) were upregulated in patients co-overexpressing TAZ-AXL-CTGF. This TAZ-AXL-CTGF gene expression signature (GES) was then applied to Connectivity Map to identify small molecules that could potentially be utilized to reverse this GES. Of the top 20 small molecules identified by connectivity map, amiloride (a potassium sparing diuretic), and tretinoin (all-trans retinoic acid) have shown therapeutic promise in inhibition of colon cancer cell growth. Using MyStats, we found that low level expression of either ANO1 or SQLE were associated with a better prognosis in patients who co-overexpressed TAZ-AXL-CTGF, and that ANO1 was an independent predictor of survival together with TAZ-AXL-CTGF. Finally, we confirmed that TAZ regulates Axl, and plays an important role in clonogenicity and non-adherent growth in vitro and tumor formation in vivo. These data suggest that TAZ could be a therapeutic target for the treatment of colon cancer.
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (ASTAR), Singapore, Singapore.
Hiu-Fung
HF
Yuen
Cian M
CM
McCrudden
Yu-Han
YH
Huang
Jill M
JM
Tham
Xiaoqian
X
Zhang
Qi
Q
Zeng
Shu-Dong
SD
Zhang
WanJin
W
Hong
D000217:Acyltransferases; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000584:Amiloride / Q000627:therapeutic use; D000075369:Anoctamin-1; D018797:Cell Cycle Proteins; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D016208:Databases, Factual; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D054852:Small Molecule Libraries / Q000627:therapeutic use; D016019:Survival Analysis; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014212:Tretinoin / Q000627:therapeutic use; D000094963:Axl Receptor Tyrosine Kinase
C476213:ANO1 protein, human; D000075369:Anoctamin-1; C526317:CCN2 protein, human; D018797:Cell Cycle Proteins; D018118:Chloride Channels; C409164:NDUFB7 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D054852:Small Molecule Libraries; D014157:Transcription Factors; C456659:YY1AP1 protein, human; D055513:Connective Tissue Growth Factor; D014212:Tretinoin; D000584:Amiloride; D009247:NADH, NADPH Oxidoreductases; D000217:Acyltransferases; C108675:TAFAZZIN protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; C000722289:AXL protein, human