ArticleCellular signalling2020
Regulation of KLF4 by posttranslational modification circuitry in endocrine resistance.
Article in Cellular signalling, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 15 citations in OpenAlex.
- ALK5 inhibition reduces HDM-induced inflammation and oxidative injury by regulating KLF4-mediated glycolysis in BEAS-2B cells.Journal of bioenergetics and biomembranes · 2026Article
- Regional and Sexual Dimorphism in Murine Skeletal Responses to Osteocytic HIF Pathway Modulation.Journal of orthopaedic research : official publication of the Orthopaedic Research Society · 2026Article
- Key roles of ubiquitination in regulating critical regulators of cancer stem cell functionality.Genes & diseases · 2025Review
- miRNA-dependent resistance mechanisms to anti-hormonal therapies in estrogen receptor-positive breast cancer patients.Molecular therapy. Oncology · 2025Review
- Metabolic Switch in Endocrine Resistant Estrogen Receptor Positive Breast Cancer.bioRxiv : the preprint server for biology · 2024Article
- Article
- MiRNA-296-5p promotes the sensitivity of nasopharyngeal carcinoma cells to cisplatin via targeted inhibition of STAT3/KLF4 signaling axis.Scientific reports · 2024Article
- Proteolytic regulation of CD73 by TRIM21 orchestrates tumor immunogenicity.Science advances · 2023Article
- Manganese Superoxide Dismutase Acetylation and Regulation of Protein Structure in Breast Cancer Biology and Therapy.Antioxidants (Basel, Switzerland) · 2022Review
- New insight into the significance of KLF4 PARylation in genome stability, carcinogenesis, and therapy.EMBO molecular medicine · 2020Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
KLF4 plays an important role in orchestrating a variety of cellular events, including cell-fate decision, genome stability and apoptosis. Its deregulation is correlated with human diseases such as breast cancer and gastrointestinal cancer. Results from recent biochemical studies have revealed that KLF4 is tightly regulated by posttranslational modifications. Here we report a new finding that KLF4 orchestrates estrogen receptor signaling and facilitates endocrine resistance. We also uncovered the underlying mechanism that alteration of KLF4 by posttranslational modifications such as phosphorylation and ubiquitylation changes tumor cell response to endocrine therapy drugs. IHC analyses using based on human breast cancer specimens showed the accumulation of KLF4 protein in ER-positive breast cancer tissues. Elevated KLF4 expression significantly correlated with prognosis and endocrine resistance. Our drug screening for suppressing KLF4 protein expression led to identification of Src kinase to be a critical player in modulating KLF4-mediated tamoxifen resistance. Depletion of VHL (von Hippel-Lindau tumor suppressor), a ubiquitin E3 ligase for KLF4, reduces tumor cell sensitivity to tamoxifen. We demonstrated phosphorylation of VHL by Src enhances proteolysis of VHL that in turn leads to upregulation of KLF4 and increases endocrine resistance. Suppression of Src-VHL-KLF4 cascade by Src inhibitor or enhancement of VHL-KLF4 ubiquitination by TAT-KLF4 (371-420AAa) peptides re-sensitizes tamoxifen-resistant breast cancer cells to tamoxifen treatment. Taken together, our findings demonstrate a novel role for KLF4 in modulating endocrine resistance via the Src-VHL-KLF4 axis.
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Registered trials
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.