Abstract 2412: The nuclear homeoprotein NKX3.1, has a novel function in the mitochondria in regulation of prostate cancer initiation

Abstract

Abstract An emerging hallmark of cancer is reprograming of energy metabolism, in which mitochondrial plasticity plays a central role. Mitochondrial plasticity, particularly in response to oxidative stress, is coordinately orchestrated by both mitochondrial- and nuclear-encoded genes. Recent reports highlight the association of mitochondrial dysfunction and prostate cancer, one of the leading causes of cancer and cancer-related death for men. One of the earliest events in prostate cancer etiology is loss of functional NKX3.1, a homeoprotein that is known to play essential roles in prostate differentiation and prostate cancer by regulation of nuclear-encoded genes. We now show that in response to oxidative stress, NKX3.1 is localized to the mitochondria where it directly protects against reactive oxygen species (ROS). NKX3.1 regulates mitochondrial function by directly binding to the D-loop (mitochondrial DNA control region) to specifically regulate mitochondrial genes coding for the electron transport chain. Moreover, we show that aberrant NKX3.1 function in the mitochondria leads to enhanced reactive oxygen species and DNA damage, both of which are reversed by metformin, a biguanide class of anti-diabetic drug that targets the mitochondrial electron transport chain. This uncovers the potential for metformin administration to individuals with NKX3.1 loss as a precision prevention approach against prostate cancer initiation. These observations highlight novel functions for homeoproteins as direct regulators of mitochondrial DNA, and demonstrate the critical role of the mitochondrial stress response in enabling prostate cancer initiation with potential novel therapeutic implications. > Citation Format: Aditya Dutta, Cory Abate-Shen. The nuclear homeoprotein NKX3.1, has a novel function in the mitochondria in regulation of prostate cancer initiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2412.