The cell cycle regulator 14-3-3σ opposes and reverses cancer metabolic reprogramming

Abstract

Summary Extensive reprogramming of cellular energy metabolism is a hallmark of cancer. Despite its importance, the molecular mechanism controlling this tumour metabolic shift remains not fully understood. Here we show that 14-3-3σ regulates cancer metabolic reprogramming and protects cells from tumourigenic transformation. 14-3-3σ opposes tumour-promoting metabolic programs by enhancing c-Myc poly-ubiquitination and subsequent degradation. 14-3-3σ demonstrates the suppressive impact on cancer glycolysis, glutaminolysis, mitochondrial biogenesis and other major metabolic processes of tumours. Importantly, 14-3-3σ expression levels predict overall and recurrence-free survival rates, tumour glucose uptake and metabolic gene expression in breast cancer patients. Thus, these results highlight that 14-3-3σ is an important regulator of tumour metabolism, and loss of 14-3-3σ expression is critical for cancer metabolic reprogramming. We anticipate that pharmacologically elevating the function of 14-3-3σ in tumours could be a promising direction for targeted anti-cancer metabolism therapy development in future.

14-3-3σ Gene Loss Leads to Activation of the Epithelial to Mesenchymal Transition Due to the Stabilization of c-Jun Protein

“…These findings are also consistent with previous reports that suggest that 14-3-3 is required for the nuclear export of another E3 ligase required for c-Jun degradation, COP1, and that this interaction might contribute to the tumor suppressive function of 14-3-3 (88, 90). Another study suggests that 14-3-3 regulates the stability of c-Myc by inducing the ubiquitin-mediated degradation of c-Myc, thus negatively regulating the activation of c-myc genes that are required for tumor progression (91). Taken together with our data, these results suggest that loss of 14-3-3 might lead to the stabiliza- (93,94).…”

Kinetic Modeling and Constrained Reconstruction of Hyperpolarized [1-13C]-Pyruvate Offers Improved Metabolic Imaging of Tumors

“…Tumor metabolism was challenged using 2DG (31) (N=9), external radiation therapy (32) (N=7), or conditional gene expression (19) (N=3); controls were tested prior to or without perturbation (N=33) or administered a negative control (N=3). All three kinetic models fit these datasets (N=55) reasonably well, as summarized in Figure 3.…”

“…1×10 6 cells carrying a Tet-On inducible 14-3-3σ expression were injected into the mammary fat pad of female nude mice. Four weeks after implantation, animals were given normal drinking water or water containing 200 μg/ml doxycycline and the effect of 14-3-3σ expression on conversion of HP pyruvate to lactate (19) was tested two weeks later.…”

Regulating the stability and localization of CDK inhibitor p27Kip1 via CSN6-COP1 axis

“…43,44,46 The cells were transfected with the indicated plasmids and incubated at 37 C with 5% (vol/vol) CO2 for 24 h. Then cycloheximide was added into the media to a final concentration of 100 mg/ml. The cells were harvested at the indicated times after CHX treatment.…”