Researchers have revealed that the KDM5D gene on the Y chromosome, which is upregulated in KRAS-mutated colorectal cancer, may be responsible for increasing tumor cell invasiveness and reducing antitumor immunity in male patients, according to a recent study published by Li et al in Nature. The new findings could provide novel insights into the unknown molecular and cellular mechanisms driving increased metastasis and poor prognosis in patients with colorectal cancer as well as how KDM5D could be used as a potential therapeutic target.
Background
There have long been prominent differences in the outcomes of male and female patients with metastatic colorectal cancer, with male patients typically experiencing higher incidence rates and worse prognoses than female patients. However, the underlying mechanisms for these differences have been mainly attributed to lifestyle and possibly sex hormones.
Although lifestyle changes may benefit male patients with colorectal cancer, many previous studies evaluating hormonal interventions to improve outcomes have yielded negative or inconclusive results—highlighting a need for a deeper mechanistic understanding of the molecular nuances that drive more aggressive disease in this patient population.
“Harnessing the experimental merits of novel colorectal cancer models, our integrated computational and functional analyses revealed that oncogenic KRAS [mutations] regulate a Y chromosome gene that promotes metastasis and tumor immune evasion in male [patients],” explained senior study author Ronald DePinho, MD, Professor of Cancer Biology in the Division of Basic Science Research and the Harry Graves Burkhart III Distinguished University Chair in Cancer Biology at The University of Texas MD Anderson Cancer Center. “We now have an actionable target meriting further investigation, providing a path to intercept that will change the natural history of the disease in [patients] with KRAS-mutated colorectal cancer,” he added.
Potential Drivers of Sex-Based Disparities
In the recent study, the researchers generated genetically engineered mouse models that closely mirrored the evolution of metastatic progression in human colorectal cancer. This included models with KRAS mutations as well as inactivated APC and p53 tumor suppressors. After observing that only models with the KRAS mutations showed sex-specific differences—with males exhibiting a higher frequency of metastasis and shorter overall survival compared with females— the researchers hypothesized that KRAS mutations were the likely drivers of these sex-based disparities.
Further, cross-species and transcriptomic analyses revealed that the KDM5D gene, which was highly upregulated in these models, possibly had significant involvement in repressing genes governing cell adhesion and antitumor immunity, promoting metastatic behavior. The researchers noted that one of the earliest steps in metastasis is the loss of cell-cell junctions, allowing cancer cells to transition into a migratory state. In KRAS-mutated metastatic colorectal cancer models, the researchers discovered that the cell junction gene AMOT was downregulated.
Additionally, patient samples demonstrated a negative correlation between AMOT and KDM5D expression in the tumors of male patients—with lower AMOT expression in KRAS-mutant colorectal cancer cell lines from male patients compared with those from female patients. Further analysis showed that KDM5D epigenetically repressed AMOT, impairing these cell junctions and enabling cancer cells to shift into a metastatic state.
Deleting KDM5D restored AMOT levels in cancer cells from laboratory models and from patients with colorectal cancer, repairing cell junctions and decreasing cancer cell invasiveness. Conversely, using a transgene to enforce KDM5D expression promoted tumor invasion in the absence of KRAS mutations.
The researchers also found that metastatic cancer cells showed decreased activity of specific genomic elements called super-enhancers—which are involved in activating transcription of certain gene clusters. Specifically, they noted a lower expression of genes involved in antigen presentation through major histocompatibility complex I. Previous studies have shown that a major histocompatibility complex deficiency may facilitate tumor immune evasion.
Conclusions
The researchers suggested that KDM5D represses the TAP1 and TAP2 genes, which normally assist in processing and presenting antigens that signal for T cells to eliminate abnormal cells. Therefore, KDM5D could enable cancer cells to avoid detection and destruction from immune cells as well as promote their ability to progress and 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,” Dr. DePinho concluded.
Disclosure: The research in this study was supported by the National Institutes of Health, the Cancer Prevention and Research Institute of Texas, the National Natural Science Foundation of China, the MD Anderson SPORE in Gastrointestinal Cancer–Developmental Research Program Award, and the Harry Graves Burkhart III Distinguished University Chair in Cancer Research. For full disclosures of the study authors, visit nature.com.
