ArticleThe Journal of clinical investigation2017
AKT-mediated stabilization of histone methyltransferase WHSC1 promotes prostate cancer metastasis.
Article in The Journal of clinical investigation, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 81 papers.
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Who cites it
81 citing papers in PubMed, 120 citations in OpenAlex.
- Genetic loss of CHD1 regulates distinct histone post-translational modifications in the development of castration-resistant prostate cancer.Neoplasia (New York, N.Y.) · 2026Article
- Histone 3 lysine 36 trimethylation by SETD2 shapes an epigenetic landscape in intestinal stem cells to orchestrate lipid metabolism and attenuate cell senescence.Cell death & disease · 2026Article
- KDM4A promotes NEPC progression through regulation of MYC expression.Cancer letters · 2026Article
- Many faces of mammalian NSD methyltransferases.Cellular & molecular biology letters · 2026Review
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- NSD Family-Mediated H3K36 Methylation in Human Cancer: Mechanisms and Therapeutic Opportunities.Biomedicines · 2025Review
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- Signaling pathways as the pivotal regulators of cisplatin resistance in tumor cells through SOX2 upregulation.Medical oncology (Northwood, London, England) · 2025Review
- H3K36me2 methyltransferase NSD2/WHSC1 promotes triple-negative breast cancer metastasis via activation of ULK1-dependent autophagy.Autophagy · 2025Article
- Discovery of a novel class NSD2 inhibitor for multiple myeloma with t(4;14)Blood neoplasia · 2025Article
- Targeting the histone reader ZMYND8 inhibits antiandrogen-induced neuroendocrine tumor transdifferentiation of prostate cancer.Nature cancer · 2025Article
- NCAPD3-mediated AKT activation regulates prostate cancer progression.FASEB bioAdvances · 2025Article
- Histone-modifying enzymes as drivers and therapeutic targets in androgen-resistant prostate cancer.Frontiers in endocrinology · 2025Review
- Dual regulation of gastrointestinal tumor progression by the IFN-γ/STAT1 pathway and prospects for targeted therapy.Frontiers in oncology · 2025Review
- Epithelial NSD2 maintains FMO-mediated taurine biosynthesis to prevent intestinal barrier disruption.Clinical and translational medicine · 2024Article
- Targeting mRNA-coding genes in prostate cancer using CRISPR/Cas9 technology with a special focus on androgen receptor signaling.Cell communication and signaling : CCS · 2024Review
- NSD2 is a requisite subunit of the AR/FOXA1 neo-enhanceosome in promoting prostate tumorigenesis.Nature genetics · 2024Article
- Histone lysine methylation modifiers controlled by protein stability.Experimental & molecular medicine · 2024Review
- Multilevel Regulation of NF-κB Signaling by NSD2 Suppresses Kras-Driven Pancreatic Tumorigenesis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
21 more citing papers are in PubMed but not listed here.
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Authors and funding
18 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Loss of phosphatase and tensin homolog (PTEN) and activation of the PI3K/AKT signaling pathway are hallmarks of prostate cancer (PCa). However, these alterations alone are insufficient for cells to acquire metastatic traits. Here, we have shown that the histone dimethyl transferase WHSC1 critically drives indolent PTEN-null tumors to become metastatic PCa. In a PTEN-null murine PCa model, WHSC1 overexpression in prostate epithelium cooperated with Pten deletion to produce a metastasis-prone tumor. Conversely, genetic ablation of Whsc1 prevented tumor progression in PTEN-null mice. Molecular characterization revealed that increased AKT activity due to PTEN loss directly phosphorylates WHSC1 at S172, preventing WHSC1 degradation by CRL4Cdt2 E3 ligase. Increased WHSC1 expression transcriptionally upregulates expression of RICTOR, a pivotal component of mTOR complex 2 (mTORC2), to further enhance AKT activity. Therefore, the AKT/WHSC1/mTORC2 signaling cascade represents a vicious feedback loop that elicits unrestrained AKT signaling. Furthermore, we determined that WHSC1 positively regulates Rac1 transcription to increase tumor cell motility. The biological importance of a WHSC1-mediated signaling cascade is substantiated by patient sample analysis in which WHSC1 signaling is tightly correlated with disease progression and recurrence. Taken together, our findings highlight a pivotal link between an epigenetic regulator, WHSC1, and key intracellular signaling molecules, AKT, RICTOR, and Rac1, to drive PCa metastasis.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.