Nucleolar Follistatin Promotes Cancer Cell Survival under Glucose-deprived Conditions through Inhibiting Cellular rRNA Synthesis

Abstract

Solid tumor development is frequently accompanied by energy-deficient conditions such as glucose deprivation and hypoxia. Follistatin (FST), a secretory protein originally identified from ovarian follicular fluid, has been suggested to be involved in tumor development. However, whether it plays a role in cancer cell survival under energy-deprived conditions remains elusive. In this study, we demonstrated that glucose deprivation markedly enhanced the expression and nucleolar localization of FST in HeLa cells. The nucleolar localization of FST relied on its nuclear localization signal (NLS) comprising the residues 64 -87. Localization of FST to the nucleolus attenuated rRNA synthesis, a key process for cellular energy homeostasis and cell survival. Overexpression of FST delayed glucose deprivation-induced apoptosis, whereas down-regulation of FST exerted the opposite effect. These functions depended on the presence of an intact NLS because the NLS-deleted mutant of FST lost the rRNA inhibition effect and the cell protective effect. Altogether, we identified a novel nucleolar function of FST, which is of importance in the modulation of cancer cell survival in response to glucose deprivation.Solid tumors over a certain size are continuously exposed to glucose deficiency and hypoxia microenvironments because of the inadequate vascular supply. The cancer cells comprising these tumors thus have to limit energy expenditure to survive under such energy-deprived conditions (1, 2). An effective way is to reduce ribosome biogenesis, the most energy-consuming process in eukaryotic cells. As a matter of fact, the rate of cellular rRNA transcription is tightly regulated in response to metabolic changes (3-5).Transcription of rRNA is catalyzed by polymerase I. Energy deprivation activates AMP-activated protein kinase, which then inactivates the polymerase I-associated transcription factor TIF-IA and thereby impairs rRNA synthesis (6). Energy depletion also triggers heterochromatin formation and rRNA gene silencing by activating the nucleolar remodeling complex (7) or the energy-dependent nucleolar silencing complex (eNoSC) (8). Inhibition of rRNA transcription by eNoSC suppresses energy expenditure and protects cells from energy deprivation-induced apoptosis (8). Meanwhile, increased production of H ϩ under hypoxia promotes the interactions between VHL and rRNA gene (rDNA) to reduce rRNA synthesis (9). Overall, cells repress rRNA transcription through multiple pathways to preserve energy and survive under energy-deprived conditions. FST 3 was originally identified from ovarian follicular fluid, with a function to suppress follicle-stimulating hormone secretion (10, 11). Later, FST was found to be expressed in a variety of tissues and organisms, participating in various processes such as cell growth, development, differentiation, and secretion (12). FST-deficient mice exhibit numerous phenotypes, including musculoskeletal and cutaneous abnormalities, and die within hours of birth because of respiratory failure (13). Recently, s...

NoD: a Nucleolar localization sequence detector for eukaryotic and viral proteins

“…In total, we collated 31 eukaryotic or viral NoLSs (including 6 human NoLSs that had not been used for training or testing previously) which are listed in Table 2, along with the position of the experimentally determined NoLSs. Sequences were filtered to remove redundancy within this dataset and redundancy with the [22], the NoLS for follistatin is reported at positions 64-87. These correspond to the positions in the protein once the signal peptide has been removed.…”

Carbon Source Metabolism and Its Regulation in Cancer Cells

“…109 Follistatin, which is traditionally recognized as a secretory protein that inactivates extracellular activin, myostatin, and bone morphogenic proteins, has been reported to promote cancer cell survival under glucose-deprived conditions through inhibiting cellular rRNA synthesis. 110–113 Glucose deprivation also stimulates O -GlcNaA modification of proteins through up-regulation of O -Linked N -acetylglucosaminyltransferase, which may play a role in nutrition sensing. 114–116 At the protein level, glucose deprivation leads to Chkl degradation through the ubiquitin-proteasome pathway, which is a key regulator in the DNA replication checkpoint.…”

Three decades of research on angiogenin: a review and perspective

“…proteins [60,61] and cytoskeletal proteins [56,62,63]; (ii) cell proliferation, including follistatin [52,64], phospholipid scramblase 1 (PLSCR1) [57], histone H3 [65], RNH1 [50], four and a half LIM domains 3 (FHL3) [54,66], and ANG receptor that is a 170-kDa cellsurface protein expressed in human endothelial cells [67] or syndecan 4 in astrocyte cells [59]; and (iii) cell apoptosis, including p53 [51], MDM2 [51], heat shock factor 1 (HSF1) [58], and RNH1 [50]. A full identification of ANG-interacting proteins may help to draw the ANG interaction maps and to better understand its roles and mechanisms.…”