Functional analysis of 11q13.5 amplicon identifies Rsf-1 (HBXAP) as a gene involved in paclitaxel resistance in ovarian cancer.
The chromosome 11q13.5 locus is frequently amplified in several types of human cancer. We have previously shown that 11q13.5 amplification was associated with significantly shorter overall survival in ovarian cancer patients, but the molecular mechanisms of how amplification of this locus contributes to disease aggressiveness remain unclear. Because ovarian cancer mortality is primarily related to resistance of chemotherapeutic agents, we screened the top six candidate genes within this amplicon for their contribution to drug resistance. Rsf-1 (also known as HBXAP) was found to be the only gene in which gene knockdown sensitized tumor cells to paclitaxel. Rsf-1 has been known to interact with hSNF2H to form an ISWI chromatin remodeling complex. We found that Rsf-1 was up-regulated in paclitaxel-resistant ovarian cancer cell lines, and Rsf-1 immunoreactivity in primary ovarian carcinoma tissues correlated with in vitro paclitaxel resistance. Ectopic expression of Rsf-1 significantly enhanced paclitaxel resistance in ovarian cancer cells. Down-regulation of hSNF2H or disruption of hSNF2H and Rsf-1 interaction enhanced paclitaxel sensitivity in tumor cells with Rsf-1 up-regulation. Rsf-1 expression altered expression in several genes and activated certain signaling pathways that may contribute to drug resistance. In conclusion, our results suggest that Rsf-1 is the major gene within the 11q13.5 amplicon that contributes to paclitaxel resistance, and the formation of the Rsf-1/hSNF2H complex is required for inducing this phenotype.
Choi
Jung Hye
JH
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA.
Sheu
Jim Jinn-Chyuan
JJ
Guan
Bin
B
Jinawath
Natini
N
Markowski
Paul
P
Wang
Tian-Li
TL
Shih
Ie-Ming
IeM
D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11; D003001:Cloning, Molecular; D004351:Drug Resistance; D005260:Female; D005784:Gene Amplification; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D009687:Nuclear Proteins / Q000235:genetics*; D021141:Nucleic Acid Amplification Techniques; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D017239:Paclitaxel / Q000627:therapeutic use*; D015534:Trans-Activators / Q000235:genetics*; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D009687:Nuclear Proteins; C452851:RSF1 protein, human; D015534:Trans-Activators; D017239:Paclitaxel