Recurrent deletion of CHD1 in prostate cancer with relevance to cell invasiveness

Abstract

Though prostate cancer is often indolent, it is nonetheless a leading cause of cancer death. Defining the underlying molecular genetic alterations may lead to new strategies for prevention or treatment. Towards this goal, we performed array-based comparative genomic hybridization (CGH) on 86 primary prostate tumors. Among the most frequent alterations not associated with a known cancer gene, we identified focal deletions within 5q21 in 15 out of 86 (17%) cases. By high-resolution tiling array CGH, the smallest common deletion targeted just one gene, the chromatin remodeler chromodomain helicase DNA-binding protein 1 (CHD1). Expression of CHD1 was significantly reduced in tumors with deletion (P=0.03), and compared with normal prostate (P=0.04). Exon sequencing analysis also uncovered nonsynonymous mutations in 1 out of 7 (14%) cell lines (LAPC4) and in 1 out of 24 (4%) prostate tumors surveyed. RNA interference-mediated knockdown of CHD1 in two nontumorigenic prostate epithelial cell lines, OPCN2 and RWPE-1, did not alter cell growth, but promoted cell invasiveness, and in OPCN2-enhanced cell clonogenicity. Taken together, our findings suggest that CHD1 deletion may underlie cell invasiveness in a subset of prostate cancers, and indicate a possible novel role of altered chromatin remodeling in prostate tumorigenesis.

CHD1 Is a 5q21 Tumor Suppressor Required for ERG Rearrangement in Prostate Cancer

“…5-7). Two groups reported independently that CHD1 has tumor-suppressive features in prostate cancer (8,9). CHD1 is involved in assembly, shifting, and removal of nucleosomes from the DNA double helix to keep it in an open and transcriptionally active state (10).…”

High nuclear karyopherin α 2 expression is a strong and independent predictor of biochemical recurrence in prostate cancer patients treated by radical prostatectomy

“…In particular, deletions at 3p13 and PTEN occur in ERG-positive and deletions of 5q21 and 6q15 in ERG-negative prostate cancers. [12][13][14][15][16][17][18][19] Interestingly, KPNA2 staining was tightly linked to PTEN and 6q15 deletions in both ERG-negative and -positive cancers. These findings might suggest that either activation of a pathway that also induces strong KPNA2 expression may facilitate PTEN and 6q15 inactivation, or PTEN and 6q15 inactivation may facilitate the development of certain molecular features, eventually leading to strong KPNA2 expression.…”

“…We and others have described a strong link of PTEN and 3p13 deletion to ERG positivity and of 5q21 and 6q15 deletions to ERG negativity. [12][13][14][15][16][17][18][19] To evaluate whether KPNA2 staining might be particularly linked to one of these genomic deletions, immunohistochemical results were compared with pre-existing findings on PTEN, 3p13, 6q15 and 5q21 deletions. The analysis of all tumors demonstrated significant associations or at least strong trends of KPNA2 expression to these deletions ( Figure 3).…”

“…4 In consequence of the detection of the TMPRSS2:ERG fusion prostate cancer is divided into subsets of fusion-positive and -negative tumors, which are linked to other genomic alterations, including deletions of PTEN and 3p13 in fusion-positive as well as deletions of 5q21 and 6q15 in fusion-negative cancers. [12][13][14][15][16][17][18][19] As these deletions have all been linked to poor patient prognosis, [12][13][14][15][16][17][18][19] we hypothesize that the prognostic value of KPNA2 might be modified by the presence or absence of these alterations. To learn more about the potential clinical utility of KPNA2 protein analysis and its association with known key molecular alterations in prostate cancer, a tissue microarray (TMA) containing 11 152 prostate cancer specimens with clinical follow-up and an attached molecular database was utilized.…”

Chromodomain Helicase DNA-Binding Proteins in Stem Cells and Human Developmental Diseases

“…CHD1 was identified as frequently deleted in the homozygous form in prostate cancer [84] and likely contributes to cellular invasiveness [85]. CHD4/Mi-2b has been found to be deleted in a high percentage (17%) of endometrial cancers and is implicated as an autoantigen in the inflammatory disorder dermatomyositis [86].…”