Promoter hypermethylation of FBXO32, a novel TGF-beta/SMAD4 target gene and tumor suppressor, is associated with poor prognosis in human ovarian cancer.
Resistance to TGF-beta is frequently observed in ovarian cancer, and disrupted TGF-beta/SMAD4 signaling results in the aberrant expression of downstream target genes in the disease. Our previous study showed that ADAM19, a SMAD4 target gene, is downregulated through epigenetic mechanisms in ovarian cancer with aberrant TGF-beta/SMAD4 signaling. In this study, we investigated the mechanism of downregulation of FBXO32, another SMAD4 target gene, and the clinical significance of the loss of FBXO32 expression in ovarian cancer. Expression of FBXO32 was observed in the normal ovarian surface epithelium, but not in ovarian cancer cell lines. FBXO32 methylation was observed in ovarian cancer cell lines displaying constitutive TGF-beta/SMAD4 signaling, and epigenetic drug treatment restored FBXO32 expression in ovarian cancer cell lines regardless of FBXO32 methylation status, suggesting that epigenetic regulation of this gene in ovarian cancer may be a common event. In advanced-stage ovarian tumors, a significant (29.3%; P<0.05) methylation frequency of FBXO32 was observed and the association between FBXO32 methylation and shorter progression-free survival was significant, as determined by both Kaplan-Meier analysis (P<0.05) and multivariate Cox regression analysis (hazard ratio: 1.003, P<0.05). Reexpression of FBXO32 markedly reduced proliferation of a platinum-resistant ovarian cancer cell line both in vitro and in vivo, due to increased apoptosis of the cells, and resensitized ovarian cancer cells to cisplatin. In conclusion, the novel tumor suppressor FBXO32 is epigenetically silenced in ovarian cancer cell lines with disrupted TGF-beta/SMAD4 signaling, and FBXO32 methylation status predicts survival in patients with ovarian cancer.
Chou
Jian-Liang
JL
Department of Life Science, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan, ROC.
Su
Her-Young
HY
Chen
Lin-Yu
LY
Liao
Yu-Ping
YP
Hartman-Frey
Corinna
C
Lai
Yi-Hui
YH
Yang
Hui-Wen
HW
Deatherage
Daniel E
DE
Kuo
Chieh-Ti
CT
Huang
Yi-Wen
YW
Yan
Pearlly S
PS
Hsiao
Shu-Huei
SH
Tai
Chien-Kuo
CK
Lin
Huey-Jen L
HJ
Davuluri
Ramana V
RV
Chao
Tai-Kuang
TK
Nephew
Kenneth P
KP
Huang
Tim H-M
TH
Lai
Hung-Cheng
HC
Chan
Michael W-Y
MW
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology; D019175:DNA Methylation; D000077209:Decitabine; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism*; D051901:Smad4 Protein / Q000378:metabolism; D013624:Taiwan / Q000453:epidemiology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D055815:Young Adult
D000964:Antimetabolites, Antineoplastic; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D009124:Muscle Proteins; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; C012589:trichostatin A; D000077209:Decitabine; C440907:FBXO32 protein, human; D044843:SKP Cullin F-Box Protein Ligases; D001374:Azacitidine; D002945:Cisplatin