Search

Sonic Hedgehog (SHH) subgroup of medulloblastoma (MB) accounts for about 25% of all subgroups of MB. Tumor microenvironment (TME) may play a key role in the tumor progression and therapeutic resistance. Tumor‐associated astrocytes (TAAs) are reshaped to drive tumor progression through multiple paracrine signals. However, the mechanism by which TAAs modulate MB cells remains elusive. Here, we illuminated that TAAs showed a specific and dynamic pattern during SHH‐MB development. Most TAAs gathered to the tumor margin during the tumor progression, rather than evenly distributed in the early‐stage tumors. We further demonstrated that lipocalin‐2 (LCN2) secreted by TAAs could promote the tumor growth and was correlated with the poor prognosis of MB patients. Knocking down LCN2 in TAAs in vitro impeded the proliferation and migration abilities of MB cells. In addition, we identified that TAAs accelerated the tumor growth by secreting LCN2 via STAT3 signaling pathway. Accordingly, blockade of STAT3 signaling by its inhibitor WP1066 and AAV‐Lcn2 shRNA, respectively, in TAAs abrogated the effects of LCN2 on tumor progression in vitro and in vivo. In summary, we for the first time clarified that LCN2, secreted by TAAs, could promote MB tumor progression via STAT3 pathway and has potential prognostic value. Our findings unveiled a new sight in reprogramming the TME of SHH‐MB and provided a potential therapeutic strategy targeting TAAs. [ABSTRACT FROM AUTHOR]

SIRT2, a cytoplasmic member of the Sirtuin family, has important roles in immunity and inflammation. However, its function in regulating the response to DNA virus infection remains elusive. Here, we find that SIRT2 is a unique regulator among the Sirtuin family that negatively modulates the cGAS‐STING‐signaling pathway. SIRT2 is down‐regulated after Herpes simplex virus‐1 (HSV‐1) infection, and SIRT2 deficiency markedly elevates the expression levels of type I interferon (IFN). SIRT2 inhibits the DNA binding ability and droplet formation of cGAS by interacting with and deacetylating G3BP1 at K257, K276, and K376, leading to the disassembly of the cGAS‐G3BP1 complex, which is critical for cGAS activation. Administration of AGK2, a selective SIRT2 inhibitor, protects mice from HSV‐1 infection and increases the expression of IFN and IFN‐stimulated genes. Our study shows that SIRT2 negatively regulates cGAS activation through G3BP1 deacetylation, suggesting a potential antiviral strategy by modulating SIRT2 activity. Synopsis: SIRT2 inhibits cGAS activation by deacetylating G3BP1, thereby disrupting their interaction. Specific inhibition of SIRT2 using AGK2 leads to potent antiviral activity against HSV‐1 infection.SIRT2 is a unique regulator among the Sirtuin family that negatively modulates the cGAS‐STING‐signaling pathway.SIRT2 inhibits the enzymatic activity, DNA binding ability, and droplet formation of cGAS by interacting with and deacetylating G3BP1.Pre‐administration of the SIRT2‐selective inhibitor AGK2 protects mice from HSV‐1 infection.AGK2 treatment increases type I IFN levels and the expression of IFN‐stimulated genes. [ABSTRACT FROM AUTHOR]

The dysregulation of the translation elongation factor families which are responsible for reprogramming of mRNA translation has been shown to contribute to tumor progression. Here, we report that the acetylation of eukaryotic Elongation Factor 1 Alpha 1 (eEF1A1/EF1A1) is required for genotoxic stress response and maintaining the malignancy of colorectal cancer (CRC) cells. The evolutionarily conserved site K439 is identified as the key acetylation site. Tissue expression analysis demonstrates that the acetylation level of eEF1A1 K439 is higher than paired normal tissues. Most importantly, hyperacetylation of eEF1A1 at K439 negatively correlates with CRC patient survival. Mechanistically, CBP and SIRT1 are the major acetyltransferase and deacetylase of eEF1A1. Hyperacetylation of eEF1A1 at K439 shows a significant tumor-promoting effect by increasing the capacity of proliferation, migration, and invasion of CRC cells. Our findings identify the altered post-translational modification at the translation machines as a critical factor in stress response and susceptibility to colorectal carcinogenesis. [ABSTRACT FROM AUTHOR]

The RIIβ subunit of cAMP‐dependent protein kinase A (PKA) is expressed in the brain and adipose tissue. RIIβ‐knockout mice show leanness and increased UCP1 in brown adipose tissue. The authors have previously reported that RIIβ reexpression in hypothalamic GABAergic neurons rescues the leanness. However, whether white adipose tissue (WAT) browning contributes to the leanness and whether RIIβ‐PKA in these neurons governs WAT browning are unknown. Here, this work reports that RIIβ‐KO mice exhibit a robust WAT browning. RIIβ reexpression in dorsal median hypothalamic GABAergic neurons (DMH GABAergic neurons) abrogates WAT browning. Single‐cell sequencing, transcriptome sequencing, and electrophysiological studies show increased GABAergic activity in DMH GABAergic neurons of RIIβ‐KO mice. Activation of DMH GABAergic neurons or inhibition of PKA in these neurons elicits WAT browning and thus lowers body weight. These findings reveal that RIIβ‐PKA in DMH GABAergic neurons regulates WAT browning. Targeting RIIβ‐PKA in DMH GABAergic neurons may offer a clinically useful way to promote WAT browning for treating obesity and other metabolic disorders. [ABSTRACT FROM AUTHOR]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2005.08.011 Byline: Wen Yong Chen (1), David H. Wang (1), RayWhay Chiu Yen (1), Jianyuan Luo (2), Wei Gu (2), Stephen B. Baylin (1) Abstract: Hypermethylated in cancer 1 (HIC1) is an epigenetically regulated transcriptional repressor that functionally cooperates with p53 to suppress age-dependent development of cancer in mice. Here we show that the mechanism by which the loss of HIC1 function promotes tumorigenesis is via activating the stress-controlling protein SIRT1 and thereby attenuating p53 function. HIC1 forms a transcriptional repression complex with SIRT1 deacetylase, and this complex directly binds the SIRT1 promoter and represses its transcription. Inactivation of HIC1 results in upregulated SIRT1 expression in normal or cancer cells; this deacetylates and inactivates p53, allowing cells to bypass apoptosis and survive DNA damage. Inhibition of SIRT1 function in cells without HIC1 abolishes the resistance to apoptosis. Since aging increases promoter hypermethylation and epigenetic silencing of HIC1, we speculate that the resultant upregulation of SIRT1 may be a double-edged sword that both promotes survival of aging cells and increases cancer risk in mammals. Author Affiliation: (1) Cancer Biology Program, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, Maryland 21231 (2) The Institute for Cancer Genetics, Columbia University, New York, New York 10032 Article History: Received 28 January 2005; Revised 8 June 2005; Accepted 8 August 2005 Article Note: (miscellaneous) Published: November 3, 2005

Results demonstrate that mammalian Sir2alpha interacts with p53 inhibiting deacetylation of p53 as well as enhancing acetylation of p53 in vivo. Data also suggest that Sir2alpha represses p53-dependent apoptosis during DNA damage and oxidative stress.