Role of desumoylation in the development of prostate cancer

Abstract

SUMO is a novel ubiquitin-like protein that can covalently modify a large number of nuclear proteins. SUMO modification has emerged as an important regulatory mechanism for protein function and localization. Sumoylation is a dynamic process that is mediated by activating (E1), conjugating (E2), and ligating (E3) enzymes and is readily reversed by a family of SUMO-specific proteases (SENPs). Since SUMO was discovered 10 years ago, the biologic contribution of this posttranslational modification has remained unclear. In this review, we report that SENP1, a member of the SENP family, is overexpressed in human prostate cancer specimens. The induction of SENP1 is observed with the chronic exposure of prostate cancer cells to androgen and/or interleukin (IL) 6. SENP1 upregulation modulates the transcriptional activity of androgen receptors (ARs) and c-Jun, as well as cyclin D1 expression. Initial in vivo data from transgenic mice indicate that overexpression of SENP1 in the prostate leads to the development of prostatic intraepithelial neoplasia at an early age. Collectively, these studies indicate that overexpression of SENP1 is associated with prostate cancer development.

Figure 1

The SUMO modification pathway. On the first step of the process, the C-terminus reveals the Gly-Gly (G-G) residues for conjugation. Aos1 and Uba2 constitute the activating enzyme complex (E1). Ubc9 is the only known SUMO-conjugating enzyme (E2). E3 denotes SUMO ligases.

Figure 2

SUMO-modified proteins. A partial list of SUMO-modified proteins is presented.

Figure 3

Sumoylation is a dynamic and reversible process. E1, SUMO-activating enzyme; E2, SUMO-conjugating enzyme; E3, SUMO ligase.

Figure 4

The human SENP family. Six SENPs share a conserved catalytic domain with four highly conserved amino acids (H, D, Q, and C) and are grouped into three families.

Figure 5

The subcellular localizations of SENPs. Overexpression images are presented.

Figure 6

ARs and the coregulators SRC1, p300, and HDAC1 are modified by SUMO.

Figure 7

SENP1 markedly enhances AR-dependent transcription. LNCaP cells cotransfected luciferase with plasmids, as indicated in the figure. After 12 hours of transfection, cells were treated with 10nmofR1881 for 24 hours, and luciferase activity was measured. Transfection efficiency was normalized using a β-galactosidase expression construct, and the results are presented as fold activation over an empty vector.

Figure 8

SENP1 induces c-Jun-dependent transcription. PC-3 cells were transfected with Gal4-luc and Gal4-DBD or Gal4-c-Jun plasmid in the absence or presence of increasing amounts of SENP1 wild-type or mutant plasmids. Luciferase activity was measured, and transfection efficiency was normalized by β-galactosidase expression.

Figure 9

Pathogenesis of prostate cancer (reproduced with permission from the New England Journal of Medicine [59]).

Figure 10

Overexpression of SENP1 in prostate cancer tissues. (A–C) In situ hybridization showed that SENP1 was overexpressed in high-grade PIN (black arrow; A) and cancer cells (black arrow; B and C), but not in normal epithelial cells (white arrow) in prostate cancer specimens. The insert in (C) was a sense probe control. (D) Immunohistochemical staining ofARs in normal prostate glands (white arrowhead) and prostate cancer (black arrowhead).

Figure 11

SENP1 regulates cyclin D1 expression in prostate cancer cells. SENP1 regulates cyclin D1 expression. (A) PC-3 cells were transfected with nonspecific siRNA or SENP1 siRNA. (B) LNCaP cells were stably transfected with an empty vector, SENP1, or SENP1 mutant. Cyclin D1 protein levels were determined in these cell clones.

Figure 12

The combination of androgen and IL-6 synergistically enhances SENP1 and PSA expression. SENP1 expression was examined in LNCaP cells treated with R1881 (A); IL-4, IL-6, or TNF-α (B); or a combination ofR1881 and IL-6 (C) for either 24 or 48 hours by real-time PCR. PSA expression was also examined in LNCaP cells treated with R1881, IL-6, or R1881 + IL-6 by enzyme-linked immunosorbent assay (D).

Figure 13

Dysplasia in the prostate of SENP1 transgenic mice. The dorsolateral and ventral lobes of the prostate from either age-matched wild-type mice (A) or 16-week-old SENP1 transgenic mice (B) were stained with hematoxylin/eosin. Abnormal growth was observed in the dorsolateral prostate of transgenic mice (highlighted with black arrow).

Figure 14

Induction of SENP1 mediates prostate cancer development. Schematic representation based on our collectively studies that indicate a relationship between prostate carcinogenesis and SENP1. Continuous exposure of prostate cancer cells to either androgen or IL-6 induces upregulation of SENP1. Elevated levels of SENP1 enhance transcriptional activity of AR and c-Jun and expression of cyclin D1. These altered pathways, in turn, involve the tumorigenesis of prostate cancer.