SENP3 is also elevated in prostate cancer and additional carcinomas, including ovarian, lung, rectum, and colon.19
The tumor suppressor protein p19ARF
is known to dictate SENP3 turnover; it initiates SENP3 phosphorylation, ubiquitylation, and subsequent proteosomal-mediated degradation.20
Loss of ARF is observed with the onset of several human cancers,21,22
and hence, deregulation of the ARF-mediated SENP3 turnover could attribute to the elevated SENP3 levels observed in various carcinomas. Alternatively, induction of SENP3 can be mediated via reactive oxygen species (ROS); ROS inhibits the ubiquitin-proteosomal mediated degradation of SENP3 to increase SENP3 protein levels.23
Increasing administration of H2
produces a dose-dependent induction of SUMO2/3, but not SUMO1, and conjugates and facilitates the redistribution of SENP3 from the nucleolus to the nucleoplasm. This relocalization changes the set of substrates deconjugated by SENP3, including the SUMO2/3-modified HIF1α. Enhanced expression of SENP3 increases HIF1α transcriptional activity but not through deconjugation of SUMO2/3-modified HIF1α. Instead, SENP3 mediates this induction of HIF1α transcription via deSUMOylation of the coregulatory protein p300. In this manner, overexpression of SENP3 facilitates the expression of HIF1α-regulated vascular endothelial growth factor (VEGF), which is critical for vascular development. When SENP3 was stably overexpressed in HeLa cells and subsequently xenografted into nude mice, the SENP3 overexpression produced more aggressive tumors, as exemplified via the greater tumor volume and angiogenesis in the xenograft animals. Hence the induction of SENP3 directly contributes to cancer progression, possibly most notably in cancers with increased ROS levels (like prostate cancer24
It is intriguing to speculate that SENP1 may play a similar role in the cancer progression. As discussed above, data from SENP1 knockout mice indicate that the loss of SENP1 potentiates HIF1α degradation and consequently lowers VEGF levels.9
Reduction of VEGF hinders development of new vasculature and contributes to the lethality of SENP1 knockout. Based on these studies from SENP1−/− MEF cells, it is feasible that induction of SENP1 carcinomas facilitates angiogenesis via enhanced stability of HIF1α; this is currently being investigated in our laboratory.
Whereas the induction of SENP1 and SENP3 in prostate cancer would favor enhanced deSUMOylation of cellular substrates, it is likely that SUMOylation would be prevalent in breast carcinomas (). Using bioinformatics analysis of published microarray data, a recent report demonstrated downregulation of SENP6 mRNA in breast tumor tissue as compared to normal tissue.25
Currently, it is unknown how onset of breast cancer elicits a change in SENP6 mRNA expression. In addition to the reduction of SENP6, mRNA of the SUMO conjugation machinery—specifically, SUMO1, Ubc9, and the E3 PIAS3—is elevated in data from this study and an additional report.25,26
Augmentation of SUMO conjugation in breast cancer cells increases tumor formation; stable overexpression of Ubc9 in the breast cancer cell line MCF7 increases SUMOylation and tumor volume when xenografted into mice.27
In contrast, decreasing SUMOylation with the expression of the dominant negative Ubc9 inhibits tumor volume in the xenograft models. It is possible that restoring reduced SENP6 levels in breast cancer cells could produce results similar to the dominant negative Ubc9 and inhibit tumor formation. Hence, in some cancers, enhancing net SUMO conjugation (possibly via downregulation of one or more SENPs) may contribute to the progression of the carcinoma.
Figure 2. Imbalance in SUMO equilibrium with the onset of cancer. Normal cell biology requires a balance in the level of SUMO modified (indicated with ) and unmodified (de ) substrates. With the onset of cancer, components of the SUMOylation or deSUMOylation machinery (more ...)