BACH1 Promotes Pancreatic Cancer Metastasis by Repressing Epithelial Genes and Enhancing Epithelial–Mesenchymal Transition

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is among the cancers with the poorest prognoses due to its highly malignant features. BTB and CNC homology 1 (BACH1) has been implicated in RAS-driven tumor formation. We focused on the role of BACH1 in PDAC, more than 90% of which have KRAS mutation. Knockdown of BACH1 in PDAC cell lines reduced cell migration and invasion, in part, by increasing E-cadherin expression, whereas its overexpression showed opposite effects. BACH1 directly repressed the expression of FOXA1 that is known to activate the expression of CDH1 encoding E-cadherin and to inhibit epithelial-to-mesenchymal transition. BACH1 also directly repressed the expression of genes important for epithelial cell adhesion including CLDN3 and CLDN4. In a mouse orthotopic implantation model, BACH1 was required for the high metastatic ability of AsPC-1 cells. IHC analysis of clinical specimens with a newly developed anti-BACH1 mAb revealed that high expression of BACH1 is a poor prognostic factor. These results suggest that the gene regulatory network of BACH1 and downstream genes including CDH1 contribute to the malignant features of PDAC by regulating epithelial-tomesenchymal transition.Significance: Greater understanding of the gene regulatory network involved in epithelial-to-mesenchymal transition of pancreatic cancer cells will provide novel therapeutic targets and diagnostic markers.

Molecular mediators of peritoneal metastasis in pancreatic cancer

“…Restoration of E-cadherin expression reverses these processes indicating a direct role for this adhesion molecule in PDA peritoneal dissemination [ 148 ]. BACH1 promotes PDA peritoneal metastasis by repressing E-cadherin and enhancing EMT, particularly in cases driven by KRAS mutation [ 81 ]. ARL4C is significantly expressed in PDA and promotes growth and metastasis of this disease [ 83 ].…”

“…In PDA, similar to ovarian and gastric cancers, loss of E-cadherin expression increases cell invasion in vitro and peritoneal dissemination in vivo , while restoration of E-cadherin expression reverses these processes [ 148 ]. As is ovarian cancer, BACH1 promotes PDA cell migration and invasion in part by repressing E-cadherin expression [ 81 ]. MSLN and MUC16 co-overexpression and mutual binding of MSLN to MUC16 markedly enhances PDA cell migration and invasion.…”

scATAC-Seq reveals epigenetic heterogeneity associated with an EMT-like process in male germline stem cells and its regulation by G9a

“…In addition, chromVAR analysis showed that the most variable TF motifs across all the cells represented EMT regulators Smarcc1, Bach1 and c-Fos (Figure 4F and G). BACH1 has been reported to promote EMT by repressing the expression of a set of epithelial genes [46]. SMARCC1 interacts with NKX6.1 to activate EMT in HeLa cells[47].…”

Prognostic value of eight immune gene signatures in pancreatic cancer patients

“…Growth factor signal transduction pathway mediated by mTOR complex 1 (mTORC1) promotes cancer metabolism through key enzymes that regulate metabolic pathways. Inhibition of mTOR C1 reduces glycolysis of cancer cells [38,39].EMT can promote tumor cell infiltration and tumor metastasis and may also make tumor cells escape apoptosis induced by some factors [40,41]. This process also plays a key role in regulating cellular plasticity in normal human tissues and tumor tissues.…”