Nucleic DHX9 cooperates with STAT1 to transcribe interferon-stimulated genes

Ren, Xiaopeng; Wang, Decai; Zhang, Guorong; Zhou, Tingyue; Wei, Zheng; Yang, Yi; Zheng, Yunjiang; Lei, Xuqiu; Tao, Wanyin; Wang, An Min; Li, Mingsong; Flavell, Richard A.; Zhu, Shu

doi:10.1126/sciadv.add5005

Cited by 17 publications

(9 citation statements)

References 62 publications

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“…Like ADAR1 and PKR, DHX9 possesses dsRBDs, a singularly unique trait among the DEAD/DEAH box RNA helicase family. Like many RNA helicases, DHX9 is important in numerous cellular processes, ranging from mRNA processing to resolution of R-Loops ( 67, 68 ), and has been shown to promote antiviral immunity by activation of the IFN-I, though those studies were not performed using cancer cell lines ( 69, 70 ). DHX9 expression is strongly correlated with ADAR1-p110 expression in breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Induction of Viral Mimicry Upon Loss of DHX9 and ADAR1 in Breast Cancer Cells

Cottrell,

Ryu,

Pierce

et al. 2024

Cancer Research Communications

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Detection of viral double-stranded RNA (dsRNA) is an important component of innate immunity. However, many endogenous RNAs containing double-stranded regions can be misrecognized and activate innate immunity. The interferon inducible ADAR1-p150 suppresses dsRNA sensing, an essential function for ADAR1 in many cancers, including breast. Although ADAR1-p150 has been well established in this role, the functions of the constitutively expressed ADAR1-p110 isoform are less understood. We used proximity labeling to identify putative ADAR1-p110 interacting proteins in breast cancer cell lines. Of the proteins identified, the RNA helicase DHX9 was of particular interest. Knockdown of DHX9 in ADAR1-dependent cell lines caused cell death and activation of the dsRNA sensor PKR. In ADAR1-independent cell lines, combined knockdown of DHX9 and ADAR1, but neither alone, caused activation of multiple dsRNA sensing pathways leading to a viral mimicry phenotype. Together, these results reveal an important role for DHX9 in suppressing dsRNA sensing by multiple pathways.

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Section: Discussionmentioning

confidence: 99%

Induction of Viral Mimicry Upon Loss of DHX9 and ADAR1 in Breast Cancer Cells

Cottrell,

Ryu,

Pierce

et al. 2024

Cancer Research Communications

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“…In steady-state conditions, DHX9 knockout precipitates R-loop-mediated genomic instability, triggering the activation of the cGAS-STING-interferon pathway and the consequent induction of ISGs. Intriguingly, under conditions of viral infection or direct interferon stimulation, DHX9 uniquely associates with the ISG promoter region, facilitating STAT1-mediated transcription of a of ISGs 67 . We think this difference is related to the intensity of the stimulus.…”

Section: Discussionmentioning

confidence: 99%

“…Dhx9 -floxed mice were generated as previously described 67 . Villin-Cre and Lgr5-EGFP-IRES-Cre ERT2 mice were obtained from the Jackson Laboratory.…”

Section: Methodsmentioning

confidence: 99%

DHX9 maintains epithelial homeostasis by restraining R-loop-mediated genomic instability in intestinal stem cells

Ren,

Liu,

Zhou

et al. 2024

Nat Commun

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Epithelial barrier dysfunction and crypt destruction are hallmarks of inflammatory bowel disease (IBD). Intestinal stem cells (ISCs) residing in the crypts play a crucial role in the continuous self-renewal and rapid recovery of intestinal epithelial cells (IECs). However, how ISCs are dysregulated in IBD remains poorly understood. Here, we observe reduced DHX9 protein levels in IBD patients, and mice with conditional DHX9 depletion in the intestinal epithelium (Dhx9ΔIEC) exhibit an increased susceptibility to experimental colitis. Notably, Dhx9ΔIEC mice display a significant reduction in the numbers of ISCs and Paneth cells. Further investigation using ISC-specific or Paneth cell-specific Dhx9-deficient mice demonstrates the involvement of ISC-expressed DHX9 in maintaining epithelial homeostasis. Mechanistically, DHX9 deficiency leads to abnormal R-loop accumulation, resulting in genomic instability and the cGAS-STING-mediated inflammatory response, which together impair ISC function and contribute to the pathogenesis of IBD. Collectively, our findings highlight R-loop-mediated genomic instability in ISCs as a risk factor in IBD.

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“…To the best of our knowledge, the present study is the first to report this finding. STAT1 (40) and BST2 (41) have previously been studied mainly as interferon-stimulated genes.…”

Section: Discussionmentioning

confidence: 99%

BST2 regulated by the transcription factor STAT1 can promote metastasis, invasion and proliferation of oral squamous cell carcinoma via the AKT/ERK1/2 signaling pathway

Shan

Shen

Wang³

et al. 2023

Int J Oncol

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Oral squamous cell carcinoma (OSCC) is one of the main types of head and neck squamous cell carcinoma. Although progress has been made in treating OSCC, it remains a threat to human health, and novel therapeutic strategies are needed to extend the lifespan of patients with OSCC. The present study, evaluated whether bone marrow stromal antigen 2 (BST2) and STAT1 were potential therapeutic targets in OSCC. Small interfering RNA (siRNA) or overexpression plasmids were used to regulate BST2 or STAT1 expression. Western blotting and reverse transcription-quantitative PCR were performed to assess changes in the protein and mRNA expression levels of signaling pathway components. The effects of BST2 and STAT1 expression changes on the migration, invasion and proliferation of OSCC cells were assessed using the scratch test assay, Transwell assay and colony formation assay in vitro, respectively. Cell-derived xenograft models were used to evaluate the impact of BST2 and STAT1 on the occurrence and development of OSCC in vivo. Finally, it was demonstrated that BST2 expression was significantly upregulated in OSCC. Furthermore, it was demonstrated that high expression of BST2 in OSCC contributed to the metastasis, invasion and proliferation of OSCC cells. Moreover, it was demonstrated that the promoter region of BST2 was regulated by the transcription factor STAT1, and that the STAT1/BST2 axis could affect the behavior of OSCC via the AKT/ERK1/2 signaling pathway. In vivo studies also demonstrated that STAT1 downregulation inhibited OSCC growth by down-regulating BST2 expression via the AKT/ERK1/2 signaling pathway.

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Nucleic DHX9 cooperates with STAT1 to transcribe interferon-stimulated genes

Cited by 17 publications

References 62 publications

Induction of Viral Mimicry Upon Loss of DHX9 and ADAR1 in Breast Cancer Cells

Induction of Viral Mimicry Upon Loss of DHX9 and ADAR1 in Breast Cancer Cells

DHX9 maintains epithelial homeostasis by restraining R-loop-mediated genomic instability in intestinal stem cells

BST2 regulated by the transcription factor STAT1 can promote metastasis, invasion and proliferation of oral squamous cell carcinoma via the AKT/ERK1/2 signaling pathway

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