hPCL3S promotes proliferation and migration of androgen-independent prostate cancer cells

Abstract

Polycomb repressive complex 2 (PRC2) allows the deposition of H3K27me3. PRC2 facultative subunits modulate its activity and recruitment such as hPCL3/ PHF19, a human ortholog of Drosophila Polycomb-like protein (PCL). These proteins contain a TUDOR domain binding H3K36me3, two PHD domains and a "Winged-helix" domain involved in GC-rich DNA binding. The human PCL3 locus encodes the fulllength hPCL3L protein and a shorter isoform, hPCL3S containing the TUDOR and PHD1 domains only. In this study, we demonstrated by RT-qPCR analyses of 25 prostate tumors that hPCL3S is frequently up-regulated. In addition, hPCL3S is overexpressed in the androgen-independent DU145 and PC3 cells, but not in the androgen-dependent LNCaP cells. hPCL3S knockdown decreased the proliferation and migration of DU145 and PC3 whereas its forced expression into LNCaP increased these properties. A mutant hPCL3S unable to bind H3K36me3 (TUDOR-W50A) increased proliferation and migration of LNCaP similarly to wt hPCL3S whereas inactivation of its PHD1 domain decreased proliferation. These effects partially relied on the up-regulation of genes known to be important for the proliferation and/or migration of prostate cancer cells such as S100A16, PlexinA2, and Spondin1. Collectively, our results suggest hPCL3S as a new potential therapeutic target in castration resistant prostate cancers.

Insights into high-risk multiple myeloma from an analysis of the role of PHF19 in cancer

“…In prostate cancer, two studies were published showing controversial data regarding the cellular localization and the role of PHF19S in cell growth and migration of the same cell lines (DU145 and PC3) [35,49]. The mRNA level of PHF19S but not PHF19L was shown to be higher in cancer tissues compared with adjacent normal tissues [49].…”

“…In prostate cancer, two studies were published showing controversial data regarding the cellular localization and the role of PHF19S in cell growth and migration of the same cell lines (DU145 and PC3) [35,49]. The mRNA level of PHF19S but not PHF19L was shown to be higher in cancer tissues compared with adjacent normal tissues [49]. In two androgen-independent prostate cancer cell lines (DU145 and PC3) compared to a nontumorigenic prostate epithelial cell line (RWPE-1) both PHF19L and PHF19S were seen to be overexpressed by western blot [35,49].…”

HIC1 (Hypermethylated in Cancer 1) modulates the contractile activity of prostate stromal fibroblasts and directly regulates CXCL12 expression

“…In a second experiment, we included these 10 tumors in a larger cohort with 20 prostate cancer samples (Supplementary Table 1) and we measured HIC1 expression levels by RT-qPCR using the normal prostate of a young (24-year old) healthy donor as control [24]. HIC1 expression was detectable in all samples.…”

“…Clinical data and patient consent were obtained by the referring physician (Supplementary Table 1). Total RNAs used in RT-qPCR analyses were extracted from frozen tissues corresponding to matched healthy prostate and neoplastic tissue obtained from 10 patients and to primary tumors obtained from 20 other patients (age ranging from 51 to 73 years; Gleason score ranging from 6 to 9; see Supplementary Table 1 for details) as previously described [24,47]. These tissues were obtained from the urological collection of the local tumor tissue bank (Tumorothèque C2RC, CHU LILLE, France) after approval by the internal review board (CSTMT 225).…”

“…These tissues were obtained from the urological collection of the local tumor tissue bank (Tumorothèque C2RC, CHU LILLE, France) after approval by the internal review board (CSTMT 225). Most of this cohort (Tumors 1-25) has been used in a previous study focusing on the expression of hPCL3S [24]. As a control, total prostate RNAs from a healthy 24-year donor were obtained from Biochain.…”