A lesser-known protein found in mice has been shown to interfere with harmful chemical modifications to genes linked to human colorectal cancer cells, suggesting potential applications for treating solid tumors, as per a recent research study.
A lesser-known protein found in mice has been shown to interfere with harmful chemical modifications to genes linked to human colorectal cancer cells, suggesting potential applications for treating solid tumors, as per a recent research study from scientists at the Johns Hopkins Kimmel Cancer Center and the Chinese Academy of Sciences.
The research, published on January 8 in the journal Nature Communications, identified that the mouse variant of a protein named STELLA successfully disrupted a critical epigenetic factor and reduced tumor growth more effectively than its human counterpart. By identifying the specific amino acids responsible for this difference in effectiveness, the team created and tested a drug strategy using those amino acids to target colorectal cancer in cell lines and in a mouse model. Epigenetics refers to chemical changes to genes that drive cancer progression without altering the DNA sequence.
“In the realm of solid tumors, which are major contributors to cancer-related deaths, there is a significant need for novel methods to therapeutically target DNA methylation anomalies,” stated Stephen Baylin, M.D., a leading author and the Virginia and D.K. Ludwig Professor of Oncology and Medicine at Johns Hopkins, as well as co-director of the Kimmel Cancer Center Genetics and Epigenetics Program. “This represents an innovative strategy to address the growing need for epigenetic therapy in cancer in a meaningful way,” added Xiangqian Kong, a principal investigator at the Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences.
The newly proposed drug strategy is the result of rigorous research aimed at discovering ways to inhibit proteins that promote cancer-specific epigenetic modifications within cells. “Epigenetics” refers to chemical changes that occur on top of genes, which do not alter the actual DNA sequence. Analogous to hardware and software in computers, DNA serves as the hardware while the epigenome functions as the software. These epigenetic modifications can influence when and how specific genes are activated or deactivated.
Just as mutations in DNA can lead to cancer, modifications in the epigenome can also provide similar outcomes. Over the past ten years, scientists have developed various therapies aimed at reversing abnormal DNA methylation to hinder cancer advancement and metastasis. While there are currently approved epigenetic therapies for blood-related cancers like leukemia, similar treatments for solid tumors are lacking.
A key epigenetic target is UHRF1, a protein often found at elevated levels in various solid tumors. UHRF1 functions as a guide that recruits another protein to add methyl groups to the DNA of tumor suppressing genes. If researchers can intercept UHRF1’s actions, they may be able to prevent or reverse destructive changes to the genome, say Baylin and Kong.
Since 2014, mounting evidence indicates that STELLA, a protein crucial for mouse embryonic development, effectively binds to UHRF1 and isolates it. With this understanding, Baylin, Kong, and their team aimed to delve deeper into how STELLA inhibits UHRF1.
They quickly noticed a difference in how the mouse version of the protein compared to its human equivalent: mouse STELLA (mSTELLA) bound strongly to UHRF1, unlike human STELLA (hSTELLA). A comparison of the two proteins revealed that mSTELLA and hSTELLA share only 31% similarity at the amino acid level.
The researchers proceeded with structural analyses and pinpointed a small peptide region responsible for the differences observed in mSTELLA and hSTELLA. They then tested to see if the peptide from mSTELLA would be effective in human cancer cells. The experiment confirmed that the mSTELLA peptide was essential for successfully blocking UHRF1 and activating tumor suppressor genes in human colorectal cancer cells.
Building upon these findings, the team rapidly moved to create a drug strategy utilizing mSTELLA for cancer treatment. They developed a lipid nanoparticle therapy, an extremely small drug delivery system made of fatty molecules, to deliver the mSTELLA peptide as mRNA into cells – a method akin to how most COVID-19 vaccines function. The therapy was shown to be effective in mice, activating tumor suppressor genes and inhibiting tumor growth.
Because UHRF1 is recognized as an oncogene in several cancer types, the implications of these results could lead to treating various cancers, state Baylin and Kong: “We are genuinely enthusiastic about advancing this work toward patient treatment.”
Additional collaborators on the study included Ying Cui, Ray-Whay Chiu Yen, and Srinivasan Yegnasubramanian from Johns Hopkins, along with Wenjing Bai, Jinxin Xu, Wenbin Gu, Danyang Wang, Weidong Rong, Xiaoan Du, Xiaoxia Li, Cuicui Xia, Qingqing Gan, Guantao He, Huahui Guo, Jinfeng Deng, Yuqiong Wu, Cheng Luo, Linping Wu, and Jinsong Liu from the Chinese Academy of Sciences in Beijing, as well as Scott Rothbart from the Van Andel Institute’s Department of Epigenetics in Grand Rapids, Michigan, where Baylin also holds a position.
This study received funding from the National Natural Science Foundation of China (grant #22107101), a grant from Bristol Myers-Squibb — Celgene, the National Institute of Environmental Health Sciences (#R01ES011858), the Samuel Waxman Cancer Research Foundation, The Hodson Trust, the National Key R&D Program of China (#2022YFA1303100, #2023YFF0724200), the Guangdong Basic and Applied Basic Research Foundation (#2021B1515420002, #2023B1212060050), the Pearl River Talents Plan (#2021QN02Y734), the Science and Technology Projects in Guangzhou (#2024A04J4358), the Open Project of State Key Laboratory of Respiratory Diseases (#SKLRD-OP-202213), the Lingang Laboratory (#LG-QS-202205-07), the Basic Research Project of the Guangzhou Institute of Biomedicine and Health (# GIBHBRP23-03, GIBHBRP24-03), and the National Cancer Institute, National Institutes of Health (#R01CA283463).
Baylin has an interest in MSP, which is licensed to MDxHealth under agreement with The Johns Hopkins University, and he and JHU are eligible to receive shares from royalties. He has also filed for a provisional patent regarding this research.
