Tanjun Tong

The Polycomb group (PcG) protein chromobox 8 (CBX8) is the subunit of Polycomb repressive complex 1 (PRC1) and recognizes the trimethylation of histone H3 on Lysine 27 (H3K27me3), and coordinates with PRC2 complex to function as epigenetic gene silencer. CBX8 plays a key role in cell proliferation, stem cell biology, cell senescence, and cancer development. However, our knowledge of CBX8 post-translational modifications remains elusive. Here, we report that protein kinase D1 (PKD1) interacts and phosphorylates CBX8 at Ser256 and Ser311 in an evolutionarily conserved motif. We found that PKD1 activation triggered by serum stimulation, Nocodazole treatment and oncogene Ras-induced cell senescence (Ras OIS) all promotes CBX8 S256/311 phosphorylation. PKD1-mediated CBX8 S256/311 phosphorylation impairs PRC1 complex integrity by reducing the binding of CBX8 to other PRC1 components BMI1 and RING1B, decreases the monoubiquitination of histone H2AK119, and results in CBX8 dissociation from its target INK4a/ARF locus and the de-repression of p16, and thus ultimately facilitates cellular senescence. CBX8 S256/311 phosphorylation also compromises hepatocellular cancer cells proliferation and migration. Collectively, these results suggest that PKD1-mediated CBX8 S256/311 phosphorylation is a key mechanism governing CBX8 function, including cell senescence and cancer cell proliferation. Financial support: This work was supported by grants from Ministry of Science and Technology of the People’s Republic of China (2018YFC2000102), and from National Natural Science Foundation of China (31871382 and 81571369).

Sirtuins, initially described as histone deacetylases and gene silencers in yeast, are now known to have many more functions and to be much more abundant in living organisms. The increasing evidence of sirtuins in the field of ageing and age-related diseases indicates that they may provide novel targets for treating diseases associated with aging and perhaps extend human lifespan. Here, we summarize some of the recent discoveries in sirtuin biology that clearly implicate the functions of sirtuins in the regulation of aging and age-related diseases. Furthermore, human sirtuins are considered promising therapeutic targets for anti-aging and ageing-related diseases and have attracted interest in scientific communities to develop small molecule activators or drugs to ameliorate a wide range of ageing disorders. In this review, we also summarize the discovery and development status of sirtuin-targeted drug and further discuss the potential medical strategies of sirtuins in delaying aging and treating age-related diseases.

Hepatocellular carcinoma (HCC) is a leading cause of cancer related deaths and lacks effective therapies. Cellular senescence acts as a barrier against cancer progression and plays an important role in tumor suppression. Senescence associated long noncoding RNAs (SAL-RNAs) are thought to be critical regulators of cancer development. Here, the long noncoding RNA (lncRNA) myocardial infarction-associated transcript (miat) was first identified as an HCC specific SALncRNA. Knockdown of miat significantly promoted cellular senescence and inhibited HCC progression. Mechanistic study revealed that SAL-miat acted as a competitive endogenous RNA (ceRNA) that upregulated the expression of sirt1 by sponging miR-22-3p. Moreover, miat downregulation activated the tumor suppressor pathway (p53/p21 and p16/pRb) and stimulated senescent cancer cells to secrete senescence-associated secretory phenotype (SASP), which contributed to inhibition of tumor cell proliferation, and resulted in the suppression of HCC tumorigenesis. Together, our study provided mechanistic insights into a critical role of miat as a miRNA sponge in HCC cellular senescence, which might offer a potential therapeutic strategy for HCC treatment.

This article has been retracted. Please see: https://doi.org/10.1093/nar/gkab403

The nucleolus is an important organelle that is responsible for the biogenesis of ribosome RNA (rRNA) and ribosomal subunits assembly. It is also deemed to be the center of metabolic control, considering the critical role of ribosomes in protein translation. Perturbations of rRNA synthesis are closely related to cell proliferation and tumor progression. Telomeric repeat-binding factor 2 (TRF2) is a member of shelterin complex that is responsible for telomere DNA protection. Interestingly, it was recently reported to localize in the nucleolus of human cells in a cell-cycle-dependent manner, while the underlying mechanism and its role on the nucleolus remained unclear. In this study, we found that nucleolar and coiled-body phosphoprotein 1 (NOLC1), a nucleolar protein that is responsible for the nucleolus construction and rRNA synthesis, interacted with TRF2 and mediated the shuttle of TRF2 between the nucleolus and nucleus. Abating the expression of NOLC1 decreased the nucleolar-resident TRF2. Besides, the nucleolar TRF2 could bind rDNA and promoted rRNA transcription. Furthermore, in hepatocellular carcinoma (HCC) cell lines HepG2 and SMMC7721, TRF2 overexpression participated in the nucleolus stress-induced rRNA inhibition and cell-cycle arrest.

Microglia-involved neuroinflammation is thought to promote brain damage in various neurodegenerative disorders. Thus, inhibition of microglial over-activation may have a therapeutic benefit for the treatment of neurodegenerative disorders. Micheliolide (MCL) is a sesquiterpene lactone which inhibits various inflammatory response. However, whether MCL can inhibit neuroinflammation caused by LPS-activated BV2 microglia has not yet been explored. In this study, we demonstrated that treatment of BV2 cells with MCL significantly repressed LPS-stimulated nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression, as well as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and nitric oxide (NO) induction. MCL also attenuated mRNA levels of multiple pro-inflammatory cytokines and mediators such as iNOS, COX-2, TNF-α, IL-6 and IL-1β. Mechanistic studies revealed that MCL suppressed LPS-stimulated the activation of IκBα/NF-κB pathway and Akt pathway. Moreover, MCL inhibited LPS-induced the activition of c-Jun N-terminal kinase (JNK), p38 MAPK kinase, and extracellular signal-regulated kinases 1/2 (ERK1/2). Meanwhile, MCL markedly promoted antioxidant protein heme oxygenase-1 (HO-1) expression by enhancing NF-E2-related factor 2 (Nrf2) activity. Together, our results imply that MCL may serve as a neuroprotective agent in neuroinflammation-related neurodegenerative disorders.

Telomeric repeat-binding factor 2 (TRF2) was reported to localize in the nucleolus of human cells in a cell cycle-dependent manner; however, the underlying mechanism remains unclear. Here, we found that nucleolar and coiled-body phosphoprotein 1 (NOLC1) interacted with TRF2 and mediated the shuttling of TRF2 between the nucleolus and nucleus in human 293T and HepG2 cells. Ablation of NOLC1 expression increased the number of nuclear TRF2 foci and decreased the nucleolar level of TRF2. Conversely, NOLC1 overexpression promoted the nucleolar accumulation of TRF2. NOLC1 overexpression also increased the number of 53BP1 foci and induced the DNA damage response. In addition, co-expression of TRF2 rescued NOLC1 overexpression-induced cell cycle arrest and apoptosis.