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Supplementary Figure from HMGN5 Escorts Oncogenic STAT3 Signaling by Regulating the Chromatin Landscape in Breast Cancer Tumorigenesis

Supplementary Table from HMGN5 Escorts Oncogenic STAT3 Signaling by Regulating the Chromatin Landscape in Breast Cancer Tumorigenesis

Cancer progression is highly dependent on the ability of cancer cell tumor formation, in which epigenetic modulation plays an essential role. However, the epigenetic factors promoting breast tumor formation are less known. Screened from three-dimensional (3D)-sphere tumor formation model, HMGN5 that regulates chromatin structures became the candidate therapeutic target in breast cancer, though its role is obscure. HMGN5 is highly expressed in 3D-spheres of breast cancer cells and clinical tumors, also an unfavorable prognostic marker in patients. Furthermore, HMGN5 controls tumor formation and metastasis of breast cancer cells in vitro and in vivo. Mechanistically, HMGN5 is governed by active STAT3 transcriptionally and further escorts STAT3 to shape the oncogenic chromatin landscape and transcriptional program. More importantly, interference of HMGN5 by nanovehicle-packaged siRNA effectively inhibits tumor growth in breast cancer cell–derived xenograft mice model. Implications: Our findings reveal a novel feed-forward circuit between HMGN5 and STAT3 in promoting breast cancer tumorigenesis and suggest HMGN5 as a novel epigenetic therapeutic target in STAT3-hyperactive breast cancer.

Background: Cancer progression is highly dependent on the ability of cancer cell tumor formation, in which epigenetic modulation plays an essential role. However, the epigenetic factors promoting breast tumor formation are less known. Screened from 3D-sphere tumor formation model, HMGN5 which regulates chromatin structures became the candidate therapeutic targets in breast cancer, though its role is obscure. Methods: The differential molecular profiles of 2D- and 3D-cultured breast cancer cell spheres were analyzed by mass spectrometry. Meanwhile, the prognostic relevance of HMGN5 was evaluated by examining the expression of HMGN5 in TCGA and a tissue microarray. Then, the oncogenic role of HMGN5 was investigated by CCK-8, trans-well, tumor sphere formation assays in vitro, and xenograft tumor growth and invasion assays in vivo. RNA-seq, Cut & Tag and bioinformatics analysis were performed to explore the molecular mechanism of HMGN5 in tumorigenesis. Luciferase reporter assays and ChIP-qPCR were performed to study the regulation of HMGN5 by STAT3. Moreover, nanoparticle-packaged siRNAs targeting HMGN5 were used to test the therapeutic effect in xenograft tumor model.Results: HMGN5 is highly expressed in 3D-spheres of breast cancer cells and clinical tumors, also an unfavorable prognostic marker in patients. Furthermore, HMGN5 controls tumor formation and metastasis of breast cancer cells in vitro and in vivo. Mechanistically, HMGN5 is governed by active STAT3 transcriptionally and further escorts STAT3 to shape oncogenic chromatin landscape and transcriptional program. More importantly, interference of HMGN5 by nanoparticle-packaged siRNA effectively inhibit tumor growth in breast cancer cell-derived xenograft mice model. Conclusion: Our findings reveal a novel feed-forward circuit between HMGN5 and STAT3 in promoting breast cancer tumorigenesis and suggest HMGN5 as a novel epigenetic therapeutic-target in STAT3-hyperactive breast cancer.

Tryptophan, an essential amino acid, has been reported that it has the potential to regulate depression-like behavior. Meanwhile, Chronic stress-induced depression also has a close relationship with gut microbiota structure and composition. In the current research, we demonstrated that a tryptophan-rich diet (0.6% tryptophan w/w) significantly attenuated depression- and anxiety-like behaviors in a chronic unpredictable mild stress (CUMS)-treated mouse model. Tryptophan supplementation improved neuroinflammation, increased expression of BDNF, and improved mitochondrial energy metabolism in the brain of CUMS-treated mice. Besides, CUMS also enhanced the kynurenine pathway, but repressed the serotonin pathway and indole pathway of tryptophan metabolism, leading to a decrease in 5-HT and indole in serum, whereas tryptophan supplementation might shift the tryptophan metabolism more toward the serotonin pathway in CUMS-treated mice. The gut microbiome was restructured by increasing the relative abundance of Lachnospiracea, Clostridium, Lactobacillus, Bifidobacterium in tryptophan-treated depressive mice. Moreover, tryptophan administration inhibited stress-induced gut barrier damage and decreased inflammatory responses in the colon. Together, our study purports the gut-brain axis as a mechanism for the potential of tryptophan to improve depression and anxiety-related behavior.