Abstract
BackgroundThe gene encoding integrator complex subunit 6 (INTS6), previously known as deleted in cancer cells 1 (DICE1, OMIM 604331) was found to be frequently affected by allelic deletion and promoter hypermethylation in prostate cancer specimens and cell lines. A missense mutation has been detected in prostate cancer cell line LNCaP. Together, these results suggest INTS6/DICE1 as a putative tumor suppressor gene in prostate cancer. In this study, we examined the growth inhibitory effects of INTS6/DICE1 on prostate cancer cells.ResultsMarkedly decreased INTS6/DICE1 mRNA levels were detected in prostate cancer cell lines LNCaP, DU145 and PC3 as well as CPTX1532 as compared to a cell line derived from normal prostate tissue, NPTX1532. Exogenous re-expression of INTS6/DICE1 cDNA in androgen-independent PC3 and DU145 cell lines substantially suppressed their ability to form colonies in vitro. This growth inhibition was not due to immediate induction of apoptosis. Rather, prostate cancer cells arrested in G1 phase of the cell cycle. Expression profiling of members of the Wnt signaling pathway revealed up-regulation of several genes including disheveled inhibitor CXXC finger 4 (CXXC4), frizzled homologue 7 (FZD7), transcription factor 7-like 1 (TCF7L1), and down-regulation of cyclin D1.ConclusionThese results show for the first time a link between INTS6/DICE1 function, cell cycle regulation and cell-cell communication involving members of the Wnt signaling pathway.
Highlights
The gene encoding integrator complex subunit 6 (INTS6), previously known as deleted in cancer cells 1 (DICE1, OMIM 604331) was found to be frequently affected by allelic deletion and promoter hypermethylation in prostate cancer specimens and cell lines
INTS6/DICE1-EGFP fusion construct (DICE1) missense mutations have been previously detected in lung and prostate cancer cell lines NCI-H2126 and LNCaP respectively, and reduced INTS6/DICE1 expression appears to be associated with CpG promoter hypermethylation in lung and prostate cancer cells [3,57]
INTS6/DICE1 mRNA expression is down-regulated in prostate cancer cells In order to reinforce DICE1 tumor suppressor function in prostate cancer, we analyzed its expression in different human androgen-dependent/-sensitive (LNCaP), androgen-independent/-insensitive (DU145, PC3, PC3-ml); and prostate cell lines isolated from prostatic primary tumor [14]
Summary
The gene encoding integrator complex subunit 6 (INTS6), previously known as deleted in cancer cells 1 (DICE1, OMIM 604331) was found to be frequently affected by allelic deletion and promoter hypermethylation in prostate cancer specimens and cell lines. A missense mutation has been detected in prostate cancer cell line LNCaP Together, these results suggest INTS6/DICE1 as a putative tumor suppressor gene in prostate cancer. Cancer Cell International 2009, 9:28 http://www.cancerci.com/content/9/1/28 ing in death (ACS, Cancer statistics, 2009) These numbers reflect the recent progress in prostate cancer therapy, they reveal the demand for more effective therapeutic strategies. The INTS6/DICE1 homologue interfered with the response to insulin-like growth factor 1 (IGF-1), and mouse and human DICE1 cDNA suppressed anchorage-independent growth of transformed mouse cells [12,13] These results suggest that INTS6/DICE1 is a tumor suppressor gene and emphasize the need to better characterize its function
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