RUNX2 Phosphorylation by Tyrosine Kinase ABL Promotes Breast Cancer Invasion

Abstract

Activity of transcription factors is normally regulated through interaction with other transcription factors, chromatin remodeling proteins and transcriptional co-activators. In distinction to these well-established transcriptional controls of gene expression, we have uncovered a unique activation model of transcription factors between tyrosine kinase ABL and RUNX2, an osteoblastic master transcription factor, for cancer invasion. We show that ABL directly binds to, phosphorylates, and activates RUNX2 through its SH2 domain in a kinase activity-dependent manner and that the complex formation of these proteins is required for expression of its target gene MMP13. Additionally, we show that the RUNX2 transcriptional activity is dependent on the number of its tyrosine residues that are phosphorylated by ABL. In addition to regulation of RUNX2 activity, we show that ABL transcriptionally enhances RUNX2 expression through activation of the bone morphogenetic protein (BMP)-SMAD pathway. Lastly, we show that ABL expression in highly metastatic breast cancer MDA-MB231 cells is associated with their invasive capacity and that ABL-mediated invasion is abolished by depletion of endogenous RUNX2 or MMP13. Our genetic and biochemical evidence obtained in this study contributes to a mechanistic insight linking ABL-mediated phosphorylation and activation of RUNX2 to induction of MMP13, which underlies a fundamental invasive capacity in cancer and is different from the previously described model of transcriptional activation.

Role of RUNX2 in breast cancer development and drug resistance (Review)

“…RUNX2 has been recognized as a master transcription factor for osteogenesis and bone metastases of invasive breast cancer (72). In highly metastatic breast cancer, RUNX2 phosphorylation has associations with the invasive capacity of MDA-MB-231 cells by modulating the activity of tyrosine kinase ABL, which is involved in the activation of the classical BMP-SMAD signaling cascades (17). It was further indicated that RUNX2 facilitates the aggressiveness and chemoresistance of TNBC and the concomitant tumorigenesis and cancer progression via activating MMP1, which thus provides a basis for developing RUNX2-MMP1 axis-based novel candidates for breast cancer diagnostics (21).…”

“…Meanwhile, the dysregulation and alteration of RUNX2 expression or activity may result in arteriosclerosis, skeletal dysplasia (e.g., cleidocranial dysplasia) and tumorigenesis (4,(12)(13)(14). For instance, RUNX2 is involved in the progression of various tumor types, such as osteosarcoma, renal cell carcinoma, gastric cancer and breast cancer (15)(16)(17)(18)(19)(20). For instance, a recent study by our group reported the facilitating effect of RUNX2 during aggressiveness and chemoresistance of TNBC cells via activating MMP1, which was significantly associated with poor prognosis (21).…”

miR-218-5p/RUNX2 Axis Positively Regulates Proliferation and Is Associated with Poor Prognosis in Cervical Cancer

“…In breast cancer, the positive regulation of metastasis through the ABL/RUNX2/MMP13 axis has been reported. ABL is a tyrosine kinase that directly binds, phosphorylates and activates RUNX2 through its SH2 domain, while activated RUNX2 promotes the expression of MMP13, which favors MDA-MB-231 cell invasion [50]. RUNX2 regulates EMT in breast cancer through the activation of the Wnt pathway [48], and in prostate cancer, hyperactivation of AKT by RUNX2 has been observed [51].…”

Identification of the Transcriptional Regulatory Role of RUNX2 by Network Analysis in Lung Cancer Cells

“…In thyroid cancer cells, HDAC6 potentiates RUNX2 transcription, stabilizing the assembly of the transcriptional complex on the RUNX2 P2 promoter [ 75 ]. In breast cancer, ABL phosphorylates RUNX2 through direct binding, activating its expression through its SH2 domain in a kinase-activity-dependent manner, and the activation the bone morphogenetic protein (BMP)-SMAD pathway, promoting tumor cell invasion [ 76 ]. MiR-196b must be significantly decreased in lung cancer to maintain tumor cell viability, migration, and invasion and EMT induction by TGF-β, PI3K/AKT/GSK3β, Smad, and JNK pathways, as Runx2 is a putative target of miR-196b [ 77 ].…”