c-Jun N-terminal kinase promotes stem cell phenotype in triple-negative breast cancer through upregulation of Notch1 via activation of c-Jun

Abstract

c-Jun N-terminal kinase (JNK) plays a vital role in malignant transformation of different cancers, and JNK is highly activated in basal-like triple-negative breast cancer (TNBC). However, the roles of JNK in regulating cancer stem-like cell (CSC) phenotype and tumorigenesis in TNBC are not well defined. JNK is known to mediate many cellular events via activating c-Jun. Here, we found that JNK regulated c-Jun activation in TNBC cells and that JNK activation correlated with c-Jun activation in TNBC tumors. Furthermore, the expression level of c-Jun was significantly higher in TNBC tumors than in non-TNBC tumors, and high c-Jun mRNA level was associated with shorter disease-free survival of patients with TNBC. Thus, we hypothesized that the JNK/c-Jun signaling pathway contributes to TNBC tumorigenesis. We found that knockdown of JNK1 or JNK2 or treatment with JNK-IN-8, an ATP-competitive irreversible pan-JNK inhibitor, significantly reduced cell proliferation, the ALDH1+ and CD44+/CD24- CSC subpopulations, and mammosphere formation, indicating that JNK promotes CSC self-renewal and maintenance in TNBC. We further demonstrated that both JNK1 and JNK2 regulated Notch1 transcription via activation of c-Jun and that the JNK/c-Jun signaling pathway promoted CSC phenotype through Notch1 signaling in TNBC. In a TNBC xenograft mouse model, JNK-IN-8 significantly suppressed tumor growth in a dose-dependent manner by inhibiting acquisition of the CSC phenotype. Taken together, our data demonstrate that JNK regulates TNBC tumorigenesis by promoting CSC phenotype through Notch1 signaling via activation of c-Jun and indicate that JNK/c-Jun/Notch1 signaling is a potential therapeutic target for TNBC.

Antineoplastic effects of histone deacetylase inhibitors in neuroendocrine cancer cells are mediated through transcriptional regulation of Notch1 by activator protein 1

“…The observation that the AP1 family protein c‐Jun activates Notch1 transcription has recently been made in triple‐negative breast cancer cell lines , therefore, consistent with our data. In similar experiments as ours, Xie et al.…”

TGF-β1 accelerates the hepatitis B virus X-induced malignant transformation of hepatic progenitor cells by upregulating miR-199a-3p

“…Because the enrichment of c-Jun and Fos activity was detected in the hepatoblast subtype of HCC arising from bipotential HPCs, this indicated that the AP-1 complex was the major driving force in tumorigenesis of the hepatoblast subtype [3]. Moreover, positive feedback regulation of OCT4 and c-Jun, resulting in the continuous expression of c-Jun, was critical for the induction of CSC-like characteristics in liver cancer [49], as seen in other cancers [50,51]. These results illustrate that the activation of c-Jun in HPCs is responsible for their malignant transformation.…”

Phosphorylation Dynamics of JNK Signaling: Effects of Dual-Specificity Phosphatases (DUSPs) on the JNK Pathway

“…As activated JNK moves into the nucleus, JNK catalyzes the phosphorylation of a protein substrate by forming a ternary complex with its downstream substrate and transferring the γ-phosphate of ATP. JNK predominately phosphorylates the N-terminal Ser63 and Ser73 residues of c-Jun, a member of activator protein 1 (AP-1) transcription factor family, thus enhancing its transcriptional activity [26,27]. Other downstream substrates of JNK are transcription factors, including members of the activating transcription factor (ATF) family, c-Myc, p53, nuclear factor of activated T-cells-4 (NFAT4), and Elk-1 and non-transcription factors, including the Bcl-2 family [28][29][30][31].…”