Touch and go: nuclear proteolysis in the regulation of metabolic genes and cancer

Abstract

The recruitment of transcription factors to promoters and enhancers is a critical step in gene regulation. Many of these proteins are quickly removed from DNA after they completed their function. Metabolic genes in particular are dynamically regulated and continuously adjusted to cellular requirements. Transcription factors controlling metabolism are therefore under constant surveillance by the ubiquitin-proteasome system, which can degrade DNA-bound proteins in a site-specific manner. Several of these metabolic transcription factors are critical to cancer cells, as they promote uncontrolled growth and proliferation. This review highlights recent findings in the emerging field of nuclear proteolysis and outlines novel paradigms for cancer treatment, with an emphasis on multiple myeloma.

Keywords: genome regulation; mitochondria; multiple myeloma; nuclear proteostasis; nuclear receptor corepressor 1; ubiquitin-proteasome system.

Figure 1

Nuclear proteolysis by the ubiquitin–proteasome system (UPS) regulates the turnover of transcription factors and plays a key role in controlling cell metabolism.

Figure 2

Proteasome‐dependent de‐repression of metabolic genes. Nuclear receptor corepressor 1 (NCoR1) is a target for degradation by the ubiquitin–proteasome system (UPS), especially at promoters of nuclear‐encoded mitochondrial genes. The E3‐ubiquitin ligase Siah2 is responsible for NCoR1 ubiquitination (1). NCoR1 dismissal (2) from the transcription factor cAMP response element‐binding protein (CREB) increases transcriptional activity at metabolic genes, possibly by allowing coactivators to bind to CREB (3). H3K27 acetylation levels increase upon NCoR1 elimination and stimulate the expression of mitochondrial genes, especially those encoding components of the respiratory chain and of substrate transporters (4) 31. We have observed rapid up‐regulation of Siah2 and removal of NCoR1 from nuclear mitochondrial promoters upon inhibition of mitochondrial activity (not shown). Licensing of NCoR1 elimination from these genomic sites may be a key element of retrograde signaling between mitochondria and the nucleus. How exactly UPS activity is regulated in this particular transcriptional context remains to be elucidated.

Figure 3

Diffuse large B‐cell lymphoma (DLBCL) can be divided based on metabolic profiling. Nuclear receptor corepressor 1 (NCoR1) mRNA expression correlates with the metabolic signature in DLBCL, suggesting a function as master repressor of oxidative phosphorylation. NCoR1 expression is 1.7‐fold higher in the glycolytic subset of DLBCL compared to the respiratory subset (P < 0.0001). Y‐axis denotes transcript expression in arbitrary units. Figure based on raw data available from the Broad Institute's Cancer Program Legacy Resource.

Figure 4

High levels of nuclear receptor corepressor 1 (NCoR1) expression are associated with a better survival of multiple myeloma patients treated with the proteasome inhibitor Velcade. Multiple myeloma (MM) patients with high expression of NCoR1 (and repressed mitochondrial signature) have a survival benefit when treated with Velcade (P < 0.0008), but not when treated with Dexamethasone (not shown). Median survival is 2.5‐fold higher in patients with high NCoR1 expression when compared to patients with low NCoR1 expression. The analysis is based on gene expression profiling of MM cells in 264 patients prior to treatment 85.

Figure 5

The ubiquitin–proteasome system (UPS) integrates genomic and metabolic function in a dynamic network. Multiple interconnections exist between the UPS, mitochondria, and the genome. Each component influences the other through several regulatory processes that are disturbed in metabolic diseases and cancer. Metabolism controls the availability of energy, but also generates cofactors and metabolites that interfere with UPS activity, such as reactive oxygen species (ROS) and free calcium 57, 97. One of the key remaining questions is how mitochondria communicate with the nucleus to adjust the expression of mitochondrial genes.