KMT2D links TGF‐β signaling to noncanonical activin pathway and regulates pancreatic cancer cell plasticity

Abstract

Although KMT2D, also known as MLL2, is known to play an essential role in development, differentiation, and tumor suppression, its role in pancreatic cancer development is not well understood. Here, we discovered a novel signaling axis mediated by KMT2D, which links TGF-β to the activin A pathway. We found that TGF-β upregulates a microRNA, miR-147b, which in turn leads to post-transcriptional silencing of KMT2D. Loss of KMT2D induces the expression and secretion of activin A, which activates a noncanonical p38 MAPK-mediated pathway to modulate cancer cell plasticity, promote a mesenchymal phenotype, and enhance tumor invasion and metastasis in mice. We observed a decreased KMT2D expression in human primary and metastatic pancreatic cancer. Furthermore, inhibition or knockdown of activin A

KRAS Promotes GLI2-Dependent Transcription during Pancreatic Carcinogenesis

“… 52 ). KMT2s are often dysregulated in pancreatic cancer and are associated with poor patient survival ( 53 , 54 ). Recruitment of KMT2s by GLI2 may be the underlying molecular event regulating this KRAS-induced gene expression.…”

Unveiling the Molecular Landscape of Pancreatic Ductal Adenocarcinoma: Insights into the Role of the COMPASS-like Complex

“…Understanding this mechanism could enable the identification of patients at risk for aggressive PDAC and the development of targeted therapies. In another investigation by S Lu et al, the role of KMT2D in pancreatic cancer was examined [108]. Utilizing small interfering RNA to knock down KMT2D expression in pancreatic cancer cell lines, the researchers assessed changes in miR-147b expression and activin A levels using RT-qPCR and ELISA, respectively.…”

“…In PDACs, KMT2D is frequently transcriptionally repressed through DNA methylation, leading to decreased expression, which correlates with increased proliferation, invasion, and migration [104][105][106][107]. Through modulation of glucose and lipid metabolism and cell plasticity, low expression levels of KMT2D cause proliferation, the epithelial-mesenchymal transition, and tumor progression in PDAC [104,108]. These suggest the tumor-suppressive role of KMT2D, supported by its association with a gene signature resembling the aggressive Moffitt basal-like subtype and indicating a poorer prognosis compared to the classical subtype [106][107][108].…”

“…Through modulation of glucose and lipid metabolism and cell plasticity, low expression levels of KMT2D cause proliferation, the epithelial-mesenchymal transition, and tumor progression in PDAC [104,108]. These suggest the tumor-suppressive role of KMT2D, supported by its association with a gene signature resembling the aggressive Moffitt basal-like subtype and indicating a poorer prognosis compared to the classical subtype [106][107][108]. In more than 80% of neoadjuvant-treated PDACs, KMT2D mutations were detected, indicating that the mutation may be responsible for treatment resistance [82].…”