Role of KMT2B and KMT2D histone 3, lysine 4 methyltransferases and DNA oxidation status in circulating breast cancer cells provide insights into cell-autonomous regulation of cancer stem cells

Abstract

Abstract Background Breast cancer cells (BCCs) can remain undetected for decades in dormancy. These quiescent cells are similar to cancer stem cells (CSCs); hence their ability to initiate tertiary metastasis. Dormancy can be regulated by components of the tissue microenvironment such as bone marrow mesenchymal stem cells (MSCs) releasing exosomes to dedifferentiate BCCs into CSCs. The exosomes cargo includes histone 3, lysine 4 (H3K4) methyltransferases, KMT2B and KMT2D. A less studied mechanism of CSC maintenance is the process of cell-autonomous regulation, leading us to examine the roles for KMT2B and KMT2D in sustaining CSCs, and their potential as drug targets. Methods Use of pharmacological inhibitor of H3K4 (WDR5-0103), knockdown (KD) of KMT2B or KMT2D in BCCs, real time PCR, western blot, response to chemotherapy. RNA-seq and flow cytometry of blood from BC patient for markers of CSCs and DNA hydroxylases. In vivo studies with a dormancy model for response to chemotherapy. Results H3K4 methyltransferases can sustain CSCs, impart chemoresistance, maintain cycling quiescence, and reduce migration and proliferation of BCCs. In vivo studies validated KMT2’s role in dormancy and identified these genes as potential drug targets. DNA methylase (DNMT), predicted within a network with KMT2 to regulate CSCs, was determined to sustain circulating CSC-like in the blood of patients. Conclusion CSCs are sustained by H3K4 methyltransferases and DNA methylation. Overall, the findings provide crucial insights into the epigenetic regulatory mechanisms underlying BC dormancy with KMT2B and KMT2D as potential therapeutic targets. We do not propose to change the standard of care, but to monitor circulating BCCs as a functional indicator for targeted treatment to prolong BC remission, which will partly address health disparity.