ArticleJournal of translational medicine2023
SMC3 epigenetic silencing regulates Rab27a expression and drives pancreatic cancer progression.
Article in Journal of translational medicine, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed, 3 citations in OpenAlex.
- Noncoding SNP rs17728461 modulates lung cancer progression via interchromosomal regulation of RAB27A expression.Oncogene · 2026Article
- Rab27: Molecular switch of tumor exosome secretion (Review).International journal of molecular medicine · 2026Review
- CircPTP4A2 (hsa_circ_0007364) facilitates non-small cell lung cancer progression by regulating miR-127-5p/SMC3.Biology direct · 2026Article
- Identification of SLC22A17 DNA methylation hotspot as a potential biomarker in cutaneous melanoma.Journal of translational medicine · 2024Article
- ZNF521 promotes acute myeloid leukemogenesis by suppressing the expression and acetylation of SMC3.Heliyon · 2024Article
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundPancreatic ductal adenocarcinoma (PDAC) is expected to soon surpass colorectal cancer as a leading cause of cancer mortality in both males and females in the US, only lagging behind lung cancer. The lethality of PDAC is driven by late diagnosis and inefficient therapies. The complex biology of PDAC involves various cellular components, including exosomes that carry molecular information between cells. Thus, recipient cells can be reprogrammed, impacting tumorigenesis. Rab27a is a GTPase responsible for the last step of exosomes biogenesis. Hence, dissecting the mechanisms that regulate the expression of Rab27a and that control exosomes biogenesis can provide fundamental insights into the molecular underpinnings regulating PDAC progression.
methodsTo assess the mechanism that regulates Rab27a expression in PDAC, we used PDAC cell lines. The biological significance of these findings was validated in PDAC genetically engineered mouse models (GEMMs) and human samples.
resultsIn this work we demonstrate in human PDAC samples and GEMMs that Rab27a expression decreases throughout the development of the disease, and that Rab27a knockout promotes disease progression. What is more, we demonstrate that Rab27a expression is epigenetically regulated in PDAC. Treatment with demethylating agents increases Rab27a expression specifically in human PDAC cell lines. We found that SMC3, a component of the cohesin complex, regulates Rab27a expression in PDAC. SMC3 methylation is present in human PDAC specimens and treatment with demethylating agents increases SMC3 expression in human PDAC cell lines. Most importantly, high levels of SMC3 methylation are associated with a worse prognosis in PDAC. Mechanistically, we identified an enhancer region within the Rab27a gene that recruits SMC3, and modulates Rab27a expression.
conclusionOverall, we dissected a mechanism that regulates Rab27a expression during PDAC progression and impacts disease prognosis.
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