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Why are male colorectal cancer patients more prone to metastasis?
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Why are male colorectal cancer patients more prone to metastasis? A study reveals the important role of histone demethylase KDM5D in gender differences in colorectal cancer.
Gender differences in non-reproductive organ cancers are very common. However, the causes of these differences and the impact of gender differences on cancer treatment are often overlooked, leading to different treatment outcomes for men and women
. Currently, the medical and biological communities generally believe that the main cause of gender differences in cancer is external environmental factors. These external influences include lifestyle, dietary habits, smoking, alcohol consumption, and so on.
For example, in general, men consume more red meat, processed meat, and other types of meat compared to women. Additionally, smoking and alcohol consumption are more common among men.
These factors may all contribute to an increased incidence of cancer. Conversely, women tend to consume more vegetables and fruits, which are associated with cancer prevention. Another factor contributing to gender differences in cancer is hormones.
Many studies have shown that male hormones are associated with a higher cancer incidence, while female hormones have the opposite effect. Furthermore, a recent clinical data analysis study found that even after excluding external factors, gender differences in cancer remained significant.
This suggests that biological differences between men and women, including hormones and sex chromosomes, are also important factors leading to gender differences in cancer.
Females have two X chromosomes, while males have one X and one Y chromosome.
The Y chromosome has only about 40% of the nucleotides of the X chromosome, with only about 55 protein-coding genes. Currently, most research on the function of the Y chromosome is limited to its role in sex determination.
However, in fact, the coding genes on the Y chromosome may have more diverse functions, especially in cancer, where Y chromosome genes are likely to contribute to gender differences in cancer.
On June 21, 2023, Ronald A. DePinho’s research team from MD Anderson Cancer Center in the United States published a research paper titled “Histone demethylase KDM5D upregulation drives sex differences in colon cancer” in the journal Nature.
The authors of the article analyzed animal models of colorectal cancer (CRC) and patient data and found that in male colorectal cancer patients with KRAS oncogene mutations, the expression of the Y chromosome gene KDM5D is upregulated, which in turn leads to the disruption of tight junction structures between cancer epithelial cells and increases the probability of cancer metastasis.
At the same time, KDM5D inhibits the presentation of cancer cell MHC I antigens, promoting the evasion of CD8+ T cell immune surveillance during the metastatic process.
The CRC mouse model used by the authors was the iKAP mouse model established by the DePinho team.
In the intestinal epithelial cells of this mouse model, tamoxifen induces the inactivation mutations of the tumor suppressor genes APC and p53.
On this basis, doxycycline induces the reversible expression of the oncogenic KRAS mutation G12D. In this mouse model, the researchers found that male mice (iKAP) with KRAS mutations had shorter survival and a higher probability of tumor development and metastasis compared to female mice.
In mice with wild-type KRAS (iAP), there were no differences in survival or tumor staging between male and female mice.
Furthermore, the researchers also observed extremely similar gender differences in CRC patients.
In patients carrying KRAS mutations, males had shorter survival than females, while this difference was not observed in patients without KRAS mutations.
Therefore, the researchers believe that KRAS mutations are a key factor leading to gender differences in CRC.
Subsequently, the researchers analyzed the transcriptome of iKAP mouse tumor cells.
By comparing in situ tumors and metastatic tumors, as well as tumors with KRAS mutations and tumors with wild-type KRAS, they identified a Y chromosome gene called KDM5D. KDM5D expression was upregulated in metastatic tumors, and KRAS mutations also upregulated KDM5D expression.
Therefore, KRAS mutations may promote CRC metastasis in males by upregulating KDM5D.
In iKAP cell lines and tumors, the researchers confirmed that KRAS mutations upregulated KDM5D expression by activating the STAT4 signaling pathway.
Next, the researchers validated the function of KDM5D in CRC metastasis through in vitro and in vivo experiments.
In in vitro experiments, knocking out KDM5D inhibited the migratory and invasive abilities of male iKAP cells, while overexpressing KDM5D increased the migratory and invasive abilities of female iKAP cells.
In in vivo experiments, the researchers used a liver metastasis model to verify the role of KDM5D in promoting CRC metastasis.
Additionally, the researchers established a transgenic mouse model with overexpression of KDM5D (iAP-KDM5D). In this model, the KRAS gene was wild-type, and the overexpression of KDM5D increased the occurrence rate of metastasis.
These results confirmed that KDM5D, as a downstream gene of KRAS, promotes CRC metastasis in males.
KDM5D is a histone demethylase that primarily functions by removing H3K4me2 and H3K4me3 from gene promoters, thereby inhibiting gene expression.
Therefore, the researchers performed transcriptome sequencing and histone modification sequencing (H3K4me2/3 ChIP-seq) on male iKAP cells with wild-type KDM5D and KDM5D knockout.
They identified a gene called AMOT, which is directly regulated by KDM5D histone demethylase activity.
The protein encoded by AMOT plays an important role in tight junction structures between cells.
The research results showed that overexpression of AMOT or knockout of KDM5D in iKAP cells could restore tight junction structures and inhibit cancer cell metastasis in in vitro and in vivo experiments.
Using electron microscopy, the researchers observed that the tight junction structures between epithelial cells in iAP-KDM5D and iKAP tumors were significantly disrupted compared to iAP tumors.
These results confirmed that KDM5D disrupts intercellular connections in cancer cells, making them more prone to dispersal and metastasis, by inhibiting the expression of AMOT.
In the analysis of histone modifications in iKAP cells, researchers found that in addition to histone methylation, histone acetylation (H3K27ac) is also suppressed by KDM5D.
Considering that the histone deacetylation function of KDM5D has never been reported, researchers speculate that KDM5D may interact with protein complexes that regulate histone acetylation to control H3K27ac.
Through immunoprecipitation coupled with mass spectrometry (IP-MS) analysis, researchers found that KDM5D can bind to SAP18 protein in the Sin3-HDAC complex.
The Sin3-HDAC complex contains HDAC1 and HDAC2 histone deacetylases, and the researchers confirmed through experiments that KDM5D can indirectly interact with HDAC1 and HDAC2.
It is well known that H3K27ac is an important mark on histones at gene enhancers. Therefore, the downregulation of H3K27ac caused by KDM5D also inhibits gene expression.
By comparing enhancers and super-enhancers (clusters of enhancers that activate gene expression more strongly) in iKAP cells expressing or not expressing KDM5D, researchers found that KDM5D inhibits the activity of a super-enhancer located in the major histocompatibility complex (MHC) gene cluster in the genome.
Further analysis revealed that KDM5D can regulate the TAP1 and TAP2 genes in this gene cluster.
These two genes are crucial for antigen presentation by MHC class I, responsible for transporting antigen fragments from the cytoplasm to the endoplasmic reticulum and loading them onto the MHC class I complex.
MHC class I complexes carrying antigens are presented on the cell surface, recognized by CD8+ T cells, and activate CD8+ T cell-mediated killing of cancer cells. Experimental data confirmed that KDM5D inhibits the expression of TAP1 and TAP2, reduces antigen presentation by cancer cells, and protects cancer cells from CD8+ T cell killing, leading to immune evasion in cancer.
In transgenic mouse tumors, researchers also observed fewer CD8+ T cells at the borders of tumors with KDM5D overexpression or KRAS mutations compared to tumors with wild-type KRAS, indicating that these tumor cells are less recognizable by the immune system, making it easier for them to invade surrounding normal tissues and form more metastases.
In summary, the groundbreaking findings of this study reveal the mechanism by which KRAS mutations lead to gender differences in CRC and the function of the Y chromosome gene KDM5D in cancer. Additionally, the study discovered a new role of KDM5D in regulating histone acetylation.
These research findings suggest that male CRC patients may need more proactive measures to prevent cancer metastasis.
For example, male patients may have a higher probability of postoperative metastasis, making postoperative chemotherapy more crucial for them.
In addition, concurrently inhibiting histone deacetylases while undergoing immunotherapy may enhance the effectiveness of immunotherapy in male patients.
Paper link: https://doi.org/10.1038/s41586-023-06254-7
Why are male colorectal cancer patients more prone to metastasis?
(source:internet, reference only)