NSD2 is a requisite subunit of the AR/FOXA1 neo-enhanceosome in promoting prostate tumorigenesis

The androgen receptor (AR) is a crucial protein in the prostate gland. It attaches to DNA and turns on genes that control normal prostate development. In healthy prostate cells, AR helps prevent excessive cell division and promotes normal cell functions, like producing prostatic fluid. However, in prostate cancer, AR's normal role is disrupted. It gets redirected to different parts of the DNA, leading to uncontrolled cell growth and other aggressive cancer features. But how this change happens is unknown. In this study, we found a protein called NSD2 that plays a key role in enabling AR's cancer-promoting activity. NSD2 is only expressed in prostate cancer cells, where it directly interacts with AR and helps it bind to new areas of DNA. This new binding pattern comprises over 65% of AR's binding sites in prostatic tumors. Consistently, inhibition of NSD2 rendered prostate cancer cells more normal-like and weakened hallmark cancerous characteristics. Blocking NSD2 also made cancer cells more reliant on a similar protein called NSD1. Inhibition of both NSD1 and NSD2 together caused the death of AR-dependent prostate cancer cells. Overall, this research identifies NSD2 as a new partner in AR's cancer-promoting activity. It also suggests that targeting both NSD1 and NSD2 could be a promising new treatment strategy for advanced prostate cancer.