Decitabine impact on the endocytosis regulator RhoA, the folate carriers RFC1 and FOLR1, and the glucose transporter GLUT4 in human tumors

Clinical Epigenetics

Razelle Kurzrock³  Ignacio I Wistuba²  Jean-Pierre Issa¹  Sanjay Gupta²  David Hong²  Jaroslav Jelinek¹  Maria I Nunez²  David J Stewart⁴ 

[1] Fels Institute for Cancer Research, Temple University, 3307 North Broad Street, Philadelphia, PA 19410, USA;University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA;University of California San Diego Moores Cancer Center, 3855 Health Sciences Dr, La Jolla, CA 92093, USA;Head, Division of Medical Oncology, The Ottawa Hospital/University of Ottawa, 501 Smyth Road, Ottawa, ON K1H 8 L6, Canada

关键词: Promoter methylation;    LINE1 methylation;    GLUT4;    FOLR1;    RFC1;    RhoA;    Decitabine;   

Others  :  790617
DOI  :  10.1186/1868-7083-6-2

 received in 2013-08-09, accepted in 2013-12-13,  发布年份 2014

【 摘 要 】

Background

In 31 solid tumor patients treated with the demethylating agent decitabine, we performed tumor biopsies before and after the first cycle of decitabine and used immunohistochemistry (IHC) to assess whether decitabine increased expression of various membrane transporters. Resistance to chemotherapy may arise due to promoter methylation/downregulation of expression of transporters required for drug uptake, and decitabine can reverse resistance in vitro. The endocytosis regulator RhoA, the folate carriers FOLR1 and RFC1, and the glucose transporter GLUT4 were assessed.

Results

Pre-decitabine RhoA was higher in patients who had received their last therapy >3 months previously than in patients with more recent prior therapy (P = 0.02), and varied inversely with global DNA methylation as assessed by LINE1 methylation (r = −0.58, P = 0.006). Tumor RhoA scores increased with decitabine (P = 0.03), and RFC1 also increased in patients with pre-decitabine scores ≤150 (P = 0.004). Change in LINE1 methylation with decitabine did not correlate significantly with change in IHC scores for any transporter assessed. We also assessed methylation of the RFC1 gene (alias SLC19A1). SLC19A1 methylation correlated with tumor LINE1 methylation (r = 0.45, P = 0.02). There was a small (statistically insignificant) decrease in SLC19A1 methylation with decitabine, and there was a trend towards change in SLC19A1 methylation with decitabine correlating with change in LINE1 methylation (r = 0.47, P <0.15). While SLC19A1 methylation did not correlate with RFC1 scores, there was a trend towards an inverse correlation between change in SLC19A1 methylation and change in RFC1 expression (r = −0.45, P = 0.19).

Conclusions

In conclusion, after decitabine administration, there was increased expression of some (but not other) transporters that may play a role in chemotherapy uptake. Larger patient numbers will be needed to define the extent to which this increased expression is associated with changes in DNA methylation.

【 授权许可】

   
2014 Stewart et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

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