Research Uncovers New Insights into Colorectal Cancer Outcomes and Identifies Key Y Chromosome Gene Involved in Metastasis and Immune Evasion.
A study conducted at The University of Texas MD Anderson Cancer Center has made a significant discovery regarding colorectal cancer (CRC) in male patients with KRAS mutations. The researchers identified a gene located on the Y chromosome that is highly active in this type of cancer, leading to increased invasiveness of tumor cells and diminished anti-tumor immunity.
The findings, recently published in the prestigious journal Nature, shed light on the longstanding mystery surrounding the molecular and cellular mechanisms underlying the heightened metastasis and poor prognosis observed in male CRC cases. The study emphasizes the role of a specific Y chromosome gene called KDM5D, which encodes an epigenetic enzyme, and reveals its unconventional function in regulating immune responses that combat tumor growth.
According to the corresponding author of the study, Dr. Ronald DePinho, who is a renowned professor of Cancer Biology, the integrated computational and functional analyses performed using innovative colorectal cancer models uncovered the influence of oncogenic KRAS on a Y chromosome gene that promotes metastasis and evades the immune system in males.
“We now have an actionable target meriting further investigation, providing a path to intercept that will change the natural history of the disease in men with KRAS-mutant colorectal cancer,” Dr. DePinho emphasized.
Sex-based disparities in the prognosis of metastatic CRC, the second leading cause of cancer-related deaths, have long been observed, with males generally experiencing higher incidence rates and poorer outcomes compared to females. Previously, these differences were primarily attributed to variations in lifestyle and, possibly, sex hormones.
Although lifestyle modifications can offer benefits to patients, numerous clinical studies evaluating hormonal interventions to improve outcomes in male CRC cases have yielded disappointing or inconclusive results. This underscores the urgent need to gain a deeper understanding of the intricate molecular mechanisms responsible for driving more aggressive disease in men.
Insights from laboratory models unveil gender-based disparities in tumor biology
The research team, led by first author Dr. Jiexi Li from the DePinho laboratory, conducted experiments using laboratory models to investigate the tumor biology differences between sexes. Dr. Li generated genetically engineered mouse models that closely mimic the metastatic progression of human colorectal cancer (CRC). These models included mice with oncogenic KRAS, as well as inactivated APC and p53 tumor suppressors, which are the most commonly mutated proteins in CRC patients.
Dr. Li, a recent graduate of the MD Anderson UTHealth Houston Graduate School of Biomedical Sciences, observed that only the models with the KRAS mutation exhibited sex-specific disparities. Male mice demonstrated a higher frequency of metastasis and shorter overall survival compared to their female counterparts. Based on these findings, Dr. Li hypothesized that the KRAS mutation played a significant role in driving these sex-based differences.
Through cross-species comparisons and transcriptomic analyses, the researchers discovered that a gene called KDM5D was significantly upregulated in these models. Further investigation revealed that KDM5D played a crucial role in suppressing genes responsible for cell adhesion and anti-tumor immunity, thereby promoting metastatic behavior.
KDM5D disrupts cell junctions through epigenetic mechanisms
KDM5D plays a pivotal role in epigenetically disrupting cell junctions, facilitating the transition to metastasis. The loss of cell-cell junctions is among the initial steps in metastasis, enabling cancer cells to adopt a migratory state. The research team identified the downregulation of AMOT, a gene responsible for cell junctions, in the KRAS-mutated metastatic cancer models.
Furthermore, in patient samples, a negative correlation was observed between AMOT and KDM5D expression in tumors from males. Notably, KRAS-mutant CRC cell lines derived from males exhibited lower AMOT expression compared to those from females. The detailed analysis demonstrated that KDM5D epigenetically suppresses AMOT, leading to the impairment of cell junctions and facilitating the transition of cancer cells into a metastatic state.
In the laboratory models, the deletion of KDM5D resulted in the restoration of AMOT levels in cancer cells, both from the models and from CRC patients. This restoration repaired the cell junctions and significantly reduced the invasiveness of cancer cells. Conversely, the enforced expression of KDM5D using a transgene promoted tumor invasion in the absence of oncogenic KRAS.
The newfound function of KDM5D impairs the immune system’s ability to recognize cancer cells
The researchers discovered that metastatic cancer cells exhibited reduced activity in specific genomic elements known as super-enhancers, which play a role in activating the transcription of gene clusters. Notably, there was a decrease in the expression of genes involved in antigen presentation through major histocompatibility complex I (MHC-I), which is a critical mechanism for tumor recognition by the immune system. Previous studies have demonstrated that deficiencies in MHC can facilitate the evasion of tumors from immune surveillance.
The study further unveiled that KDM5D suppresses the TAP1 and TAP2 genes, which are typically responsible for processing and presenting antigens that trigger T cells to eliminate abnormal cells. Consequently, KDM5D operates in this context to enable cancer cells to evade detection and destruction by immune cells, thereby promoting their progression and ability to metastasize.
“Not only does this explain sex-specific differences, but our work uncovered an entirely new biochemical function for histone demethylases in regulating histone acetylation at super-enhancers controlling immune system genes,” commented DePinho.
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