Sox9 directs divergent epigenomic states in brain tumor subtypes

Sardar, Debosmita; Chen, Hsiao‐Chi; Reyes, Amanda Neumann; Varadharajan, Srinidhi; Jain, Antrix; Mohila, Carrie A.; Curry, Rachel; Lozzi, Brittney; Rajendran, Kavitha; Cervantes, Alexis; Yu, Kwanha; Jalali, Ali; Rao, Ganesh; Mack, Stephen C.; Deneen, Benjamin

doi:10.1073/pnas.2202015119

Cited by 13 publications

(6 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Synaptic changes in neurons affect chromatin accessibility ( 30 , 49 , 50 ), and it is likely that classic histone acetylation and methylation states are also modified in astrocytes by neuronal activity. Indeed, Sox9 has been implicated in the regulation of epigenomic states in brain tumors ( 51 ). In olfactory circuits, a few studies have investigated the serotonergic system in the modulation of olfactory processing ( 52 , 53 ).…”

Section: Discussionmentioning

confidence: 99%

Induction of astrocytic Slc22a3 regulates sensory processing through histone serotonylation

Sardar

Cheng

Woo

et al. 2023

Science

Self Cite

View full text Add to dashboard Cite

Neuronal activity drives alterations in gene expression within neurons, yet how it directs transcriptional and epigenomic changes in neighboring astrocytes in functioning circuits is unknown. We found that neuronal activity induces widespread transcriptional up-regulation and down-regulation in astrocytes, highlighted by the identification of Slc22a3 as an activity-inducible astrocyte gene that encodes neuromodulator transporter Slc22a3 and regulates sensory processing in the mouse olfactory bulb. Loss of astrocytic Slc22a3 reduced serotonin levels in astrocytes, leading to alterations in histone serotonylation. Inhibition of histone serotonylation in astrocytes reduced the expression of γ-aminobutyric acid (GABA) biosynthetic genes and GABA release, culminating in olfactory deficits. Our study reveals that neuronal activity orchestrates transcriptional and epigenomic responses in astrocytes while illustrating new mechanisms for how astrocytes process neuromodulatory input to gate neurotransmitter release for sensory processing.

show abstract

Section: Discussionmentioning

confidence: 99%

Induction of astrocytic Slc22a3 regulates sensory processing through histone serotonylation

Sardar

Cheng

Woo

et al. 2023

Science

Self Cite

View full text Add to dashboard Cite

show abstract

“…Targeting SOX9 in prostate cancer could be a promising therapeutic approach to inhibit tumor growth and metastasis. Additionally, SOX9 is upregulated in glioblastoma, a highly aggressive brain tumor, where it contributes to tumor invasiveness and poor patient prognosis [135,136]. It controls genes associated with glioblastoma cell migration, invasion, and angiogenesis.…”

Section: Sox9mentioning

confidence: 99%

Mapping Heterogeneity of Hepatocellular Carcinoma by Investigating Hepatocyte-Specific Genes/TFs/Pathways Across Cellular and Tumor Landscapes

Shafi,

Rajpar,

Zafar

et al. 2024

Preprint

View full text Add to dashboard Cite

Background: Hepatocellular carcinoma (HCC) presents challenges due to tumor heterogeneity and therapeutic resistance. Understanding the molecular mechanisms driving heterogeneity is crucial. Key transcription factors (HNF4A, HNF1A, FOXA1/2, etc.) and signaling pathways (Wnt/β-catenin, FGF, HGF, etc.) are dysregulated in HCC. Dysregulation disrupts hepatocyte genetic programming, leading to heterogeneous cell populations. Investigating these mechanisms offers insights for targeted therapies and improving patient outcomes in HCC. Methods: Databases, including PubMed, MEDLINE, Google Scholar, and open access/ subscription-based journals were searched for published articles without any date restrictions, to trace the emergence of HCC heterogeneity by investigating the hepatocyte-specific genes/TFs/signaling pathways across cellular and tumor landscapes. Based on the criteria mentioned in the methods section, studies were systematically reviewed to investigate HCC Heterogeneity. This study adheres to relevant PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). Results: This study into hepatocellular carcinoma (HCC) revealed dysregulation of key transcription factors (TFs) and signaling pathways. Transcription factors HNF4A, HNF1A, FOXA1/2, CEBPA, GATA4/6, PROX1, SOX9, HNF6/Onecut1, and ONECUT2/HNF6β showed altered expression patterns, disrupting hepatocyte genetic programming and promoting heterogeneous cell populations in HCC. Dysregulated Wnt/β-catenin, FGF, HGF, TGF-β, and Hippo signaling pathways influenced cellular fate decisions and interactions with the tumor microenvironment, further contributing to HCC heterogeneity. Dysregulated NOTCH signaling and TBX3/18 transcription factors highlighted the complexity of HCC heterogeneity. This study points to the critical role of dysregulated TFs and signaling pathways in driving HCC heterogeneity and transdifferentiation, providing insights for targeted therapeutic interventions to improve patient outcomes. Conclusion: The decline in the gene expression of hepatocyte cell type-specific genes dysregulates the genetic programing of hepatocytes involved in cell type-specific homeostasis. The multiple roles of every gene/TF begin to manifest themselves causing the emergence of heterogeneity. The dysregulation of hepatocyte-specific genes and signaling pathways in hepatocellular carcinoma (HCC) disrupts cellular homeostasis, leading to the emergence of heterogeneity and transdifferentiation. Key transcription factors like HNF4A, HNF1A, and FOXA1/2, along with pathways such as Wnt/β-catenin and Hippo signaling, play crucial roles. This disruption sets the stage for diverse cellular phenotypes within the tumor microenvironment. Understanding these molecular mechanisms is vital for developing targeted therapeutic strategies to address HCC heterogeneity and improve patient outcomes.

show abstract

“…In the study described, exosomes acted in a way similar to the mechanisms previously indicated by other authors: sensitive cancer cells became resistant to oxaliplatin by accumulating exosomes with high circ_0032821 expression and by actively regulating the miR-515-5p/SOX9 axis [ 117 ]. SOX9 has strong oncogenic properties associated with the growth and metastasis of several types of cancer [ 130 , 131 , 132 , 133 , 134 , 135 ]. Hence, modulation of its activity at the exosomal level may also positively affect counteracting resistance to platinum-containing chemotherapeutic agents.…”

Section: Exosomes As Chemoresistance Mediatorsmentioning

confidence: 99%

Small Extracellular Vesicles and Their Involvement in Cancer Resistance: An Up-to-Date Review

Słomka

Kornek

Cho

2022

Cells

View full text Add to dashboard Cite

In recent years, tremendous progress has been made in understanding the roles of extracellular vesicles (EVs) in cancer. Thanks to advancements in molecular biology, it has been found that the fraction of EVs called exosomes or small EVs (sEVs) modulates the sensitivity of cancer cells to chemotherapeutic agents by delivering molecularly active non-coding RNAs (ncRNAs). An in-depth analysis shows that two main molecular mechanisms are involved in exosomal modified chemoresistance: (1) translational repression of anti-oncogenes by exosomal microRNAs (miRs) and (2) lack of translational repression of oncogenes by sponging of miRs through long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs). At the cellular level, these processes increase the proliferation and survival of cancer cells and improve their ability to metastasize and resist apoptosis. In addition, studies in animal models have shown enhancing tumor size under the influence of exosomal ncRNAs. Ultimately, exosomal ncRNAs are responsible for clinically significant chemotherapy failures in patients with different types of cancer. Preliminary data have also revealed that exosomal ncRNAs can overcome chemotherapeutic agent resistance, but the results are thoroughly fragmented. This review presents how exosomes modulate the response of cancer cells to chemotherapeutic agents. Understanding how exosomes interfere with chemoresistance may become a milestone in developing new therapeutic options, but more data are still required.

show abstract

Sox9 directs divergent epigenomic states in brain tumor subtypes

Cited by 13 publications

References 52 publications

Induction of astrocytic Slc22a3 regulates sensory processing through histone serotonylation

Induction of astrocytic Slc22a3 regulates sensory processing through histone serotonylation

Mapping Heterogeneity of Hepatocellular Carcinoma by Investigating Hepatocyte-Specific Genes/TFs/Pathways Across Cellular and Tumor Landscapes

Small Extracellular Vesicles and Their Involvement in Cancer Resistance: An Up-to-Date Review

Contact Info

Product

Resources

About