Researchers have identified a significant factor that contributes to the malfunction of a usually normal protein, subsequently leading to cancer. They discovered that NSD2, a protein, modifies the activity of the androgen receptor, which plays a crucial role in the proper development of the prostate. When the androgen receptor interacts with NSD2, it triggers rapid cellular division and growth, which can result in prostate cancer. This research opens up possible new avenues for targeting prostate cancer through therapy.
Researchers at the University of Michigan Health Rogel Cancer Center have pinpointed a major reason why a typically normal protein misbehaves and promotes cancer.
The research revealed that the protein NSD2 changes how the androgen receptor operates, which is essential for the normal development of the prostate. When the androgen receptor links with NSD2, it accelerates cell division and growth, potentially leading to prostate cancer. Published in Nature Genetics, this study may pave the way for innovative therapeutic approaches to prostate cancer.
The results shed light on a phenomenon that was not fully understood before. Normally, the androgen receptor helps manage prostate development by signaling cells to stop growing and maintain a healthy prostate. However, in the case of cancer, the androgen receptor takes on an opposing function: it urges cells to keep growing, thus promoting cancer progression.
“Our study is among the first to provide a molecular explanation for this dual role of the androgen receptor,” stated the study’s lead author Abhijit Parolia, Ph.D., Rogel fellow and assistant professor of pathology at Michigan Medicine. “NSD2 serves as a cancer-specific partner for the androgen receptor, effectively reprogramming its function to facilitate prostate cancer progression.”
The researchers initiated their investigation with CRISPR screening to identify cofactors linked to the androgen receptor and prostate cancer. They examined the enhanceosome—a complex comprising various proteins such as transcription factors and other epigenetic elements—that assembles on the DNA at particular locations to promote gene expression. This was compared with the neo-enhanceosome, a similar structure, where cancer-related transcription factors infiltrate and disrupt the precise arrangement, leading to the expression of cancer-driving genes.
Typically, the androgen receptor resides on specific sites within the DNA. However, in the presence of NSD2, the positioning of the androgen receptor “enhanceosome” shifts, placing it adjacent to areas linked to known cancer-promoting genes and factors.
“This machinery interacts with genes that play a role in the onset of prostate cancer, including androgen receptor, ERG, and FOXA1. They utilize this machinery to control oncogenic expression. We are now exploring ways to indirectly target these crucial genes by influencing epigenetic factors like NSD2,” explained study co-senior author Arul M. Chinnaiyan, M.D., Ph.D., the director of the Michigan Center for Translational Pathology and S.P. Hicks Professor of Pathology at Michigan Medicine.
Researchers discovered that NSD2 is present in prostate cancer cells but is absent in normal prostate cells. While NSD2 was already recognized for its role in metastatic prostate cancer, this study is the first to demonstrate its essential role in the early stages of prostate cancer development.
Using various methods to reduce or eliminate NSD2 expression in prostate cancer cells, the team found that this action returned the cells to a more normal state, decelerating the growth and spread of the cancerous cells, although it did not eradicate the cancer entirely. They also observed that a related protein called NSD1 collaborates with NSD2.
A compound that degrades both NSD1 and NSD2 effectively targeted prostate cancer cell lines, destroying them selectively while sparing normal cells. However, further development is necessary, as the initial version could not be tested on a mouse model.
“By degrading NSD1 and NSD2, we can more directly target cancer and protect normal tissue,” Chinnaiyan noted. “Our research indicates that if we can create agents targeting NSD1 and NSD2, these could potentially be used alongside FDA-approved androgen receptor blockers, enhancing treatment effectiveness.”
Additional authors include Sanjana Eyunni, Brijesh Kumar Verma, Eleanor Young, Yihan Liu, Lianchao Liu, James George, Shweta Aras, Chandan Kanta Das, Rahul Mannan, Reyaz ur Rasool, Erick Mitchell-Velasquez, Somnath Mahapatra, Jie Luo, Sandra E. Carson, Lanbo Xiao, Prathibha R. Gajjala, Sharan Venkatesh, Mustapha Jaber, Xiaoju Wang, Tongchen He, Yuanyuan Qiao, Matthew Pang, Yuping Zhang, Jean Ching-Yi Tien, Micheala Louw, Mohammed Alhusayan, Xuhong Cao, Omid Tavana, Caiyun Hou, Zhen Wang, Ke Ding, Irfan A. Asangani.
This research was supported by various organizations including the Prostate Cancer Foundation; National Cancer Institute grants P50-CA186786, R35 CA231996, P30 CA046592, R00 CA187664, K00 CA245825, R01 CA249210-0; Department of Defense grants W81XWH-21-1-0500, W81XWH-17-0404; Howard Hughes Medical Institute, and the American Cancer Society. The Rogel Cancer Center Flow Cytometry Shared Resource also provided support for this work.
