KMT2D links TGF-β signaling to noncanonical activin pathway and regulates pancreatic cancer cell plasticity
Recommended Citation
Lu S, Kim HS, Cao Y, Bedi K, Zhao L, Narayanan IV, Magnuson B, Gu Y, Yang J, Yi Z, Babaniamansour S, Shameon S, Xu C, Paulsen MT, Qiu P, Jeyarajan S, Ljungman M, Thomas D, Dou Y, Crawford H, di Magliano MP, Ge K, Yang B, and Shi J. KMT2D links TGF-β signaling to noncanonical activin pathway and regulates pancreatic cancer cell plasticity. Int J Cancer 2023.
Document Type
Article
Publication Date
8-1-2023
Publication Title
International journal of cancer.
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 reversed the protumoral role of KMT2D loss. These findings support a tumor-suppressive role of KMT2D in pancreatic cancer and identify miR-147b and activin A as novel therapeutic targets.
Medical Subject Headings
Humans; Animals; Mice; Cell Plasticity; Cell Line, Tumor; MicroRNAs; Pancreatic Neoplasms; Transforming Growth Factor beta; Activins
PubMed ID
37140208
ePublication
ePub ahead of print
Volume
153
Issue
3
First Page
552
Last Page
570
