HDAC2 Facilitates Pancreatic Cancer Metastasis

Abstract

The mortality of patients with pancreatic ductal adenocarcinoma (PDAC) is strongly associated with metastasis, a multi-step process that is incompletely understood in this disease. Although genetic drivers of PDAC metastasis have not been defined, transcriptional and epigenetic rewiring can contribute to the metastatic process. The epigenetic eraser histone deacetylase 2 (HDAC2) has been connected to less differentiated PDAC, but the function of HDAC2 in PDAC has not been comprehensively evaluated. Using genetically defined models, we show that HDAC2 is a cellular fitness factor that controls cell cycle in vitro and metastasis in vivo, particularly in undifferentiated, mesenchymal PDAC cells.Unbiased expression profiling detected a core set of HDAC2-regulated genes. HDAC2 controlled expression of several pro-survival receptor tyrosine kinases connected to mesenchymal PDAC, including PDGFRα, PDGFRβ, and EGFR. The HDAC2-maintained program disabled the tumor-suppressive arm of the TGFβ-pathway, explaining impaired metastasis formation of HDAC2-deficient PDAC. This data identifies HDAC2 as a tractable player in the PDAC metastatic cascade. The complexity of the function of epigenetic regulators like HDAC2 implicates that an increased understanding of these proteins is needed for implementation of effective epigenetic therapies. SignificanceHDAC2 has a context-specific role in undifferentiated PDAC and its capacity to disseminate systemically, implicating HDAC2 as targetable protein to prevent metastasis.Research.

The HDAC2–MTA3 interaction induces nonsmall cell lung cancer cell migration and invasion by targeting c‐Myc and cyclin D1

“…HDACs can regulate the progression of cancer cells 16 and HDAC2 is a Class I HDAC. Several studies have suggested that HDAC2 is crucial in cancer development 28–30 . However, the specific function of HDAC2 in NSCLC has not been comprehensively evaluated.…”

Emerging Role of Epigenetic Alterations as Biomarkers and Novel Targets for Treatments in Pancreatic Ductal Adenocarcinoma

“…The epigenetic eraser histone deacetylase 2 (HDAC2) has previously been shown to be connected to undifferentiated pancreatic cancer [65,66]. A more recent study explored the role of this enzyme with regards to PDAC metastasis [67]. In this paper, the authors demonstrated that HDAC2 controlled metastasis in a genetically engineered mouse model, where the metastatic burden in Hdac2 deficient mice was drastically reduced.…”

HDAC2 as a target for developing anti-cancer drugs

“…HDAC2 regulated the expression of receptor tyrosine kinases, including platelet growth factor receptor α (PDGFRα), PDGFRβ, and epidermal growth factor receptor (EGFR) [31] . Epidermal growth factor (EGF) increased the expression of creatine kinase α (CK2α), which in turn, increased the expression of HDAC2 in HCC [32] .…”

“…Thus, HDAC2 might mediate EGFR signaling to promote cancer cell proliferation. HDAC2 suppressed the anti-oncogenic transforming growth factor β signaling pathway and mediated pancreatic ductal adenocarcinoma metastasis [31] . The SIN3 transcriptional regulator family 3 A (SIN3A)-HDAC1/2 transcription repressor complex silenced bone morphogenetic protein 6 (BMP6) expression, which increased the metastatic potential and oncogenic potential of melanoma cells by suppressing BMP6-activated mothers against DPP homolog 5 signaling [33] .…”