Effect of Jmjd6 silencing in PyMT41C-cells. A) Real-Time PCR showing the levels of Jmjd6 in PyMT-41C cells transfected with non-targeting siRNA (siCtr) or specific for Jmjd6. Graph is the average of two independent experiments. Two-tailed unpaired t student test was applied to calculate statistical significance. B) Western blot performed on conditioned medium collected from PyMT-41C transfected as in A). Red Ponceau is shown as loading control. C) IF to detect ANXA1 levels and D) lipid droplet formation in cell transfected as in A).
Funding
Associazione Italiana per la Ricerca sul Cancro (AIRC)
HORIZON EUROPE Marie Sklodowska-Curie Actions (MSCA)
Agenzia Italiana del Farmaco, Ministero della Salute (AIFA)
ARTICLE ABSTRACT
Breast cancer is the most common type of cancer in women worldwide, with the luminal subtype being the most widespread. Although characterized by better prognosis compared with other subtypes, luminal breast cancer is still considered a threatening disease due to therapy resistance, which occurs via both cell- and non–cell-autonomous mechanisms. Jumonji domain-containing 6, arginine demethylase and lysine hydroxylase (JMJD6) is endowed with a negative prognostic value in luminal breast cancer and, via its epigenetic activity, it is known to regulate many intrinsic cancer cell pathways. So far, the effect of JMJD6 in molding the surrounding microenvironment has not been explored.Here, we describe a novel function of JMJD6 showing that its genetic inhibition in breast cancer cells suppresses lipid droplet formation and ANXA1 expression, via estrogen receptor alpha and PPARα modulation. Reduction of intracellular ANXA1 results in decreased release in the tumor microenvironment (TME), ultimately preventing M2-type macrophage polarization and tumor aggressiveness.
Our findings identify JMJD6 as a determinant of breast cancer aggressiveness and provide the rationale for the development of inhibitory molecules to reduce disease progression also through the remodeling of TME composition.
