*For medical professionals only
Traditionally, cancer has been thought to originate from the accumulation of somatic mutations, but in recent years, many studies have found that cancer development and susceptibility are inseparable from a large number of epigenomic changes.
Today, epigenetic changes can be used as biomarkers for cancer and can even be targeted by cancer treatments, which can be inferred that epigenetic changes have a causal role in cancer.
However, no studies have proven that pure epigenetic mechanisms can drive tumorigenesis.
Today, a team from the University of Montpellier in France published an article in the journal Nature, in which researchers confirmed for the first time in Drosophila that transient epigenetic changes are sufficient to induce irreversible cancer transformation, which is related to the irreversible deinhibition of some cancer driver genes.
Diagram of the title of the dissertation
The polycomb protein family (PcG) is an important epigenetic factor, PcG forms two major types of complexes, polycomb protein repressor complex 1/2 (PRC1/2), which regulates gene fate during development, and PcG dysfunction is associated with cancer. PcG is highly conserved in both Drosophila and humans, and most of the components are encoded by a single gene, making it an ideal research subject.
THE RESEARCHERS ESTABLISHED A HEAT-SENSITIVE RNA INTERFERENCE SYSTEM THAT COULD TARGET THE PH SUBUNIT EXPRESSION OF PRC1. The PH protein in the eye disc of Drosophila larvae is depleted within 24 hours at 29 °C and returns to normal levels within 48 hours at 18 °C.
AS EXPECTED, SUSTAINED KNOCKDOWN OF THE PH PROTEIN RESULTED IN 100% TRANSFORMATION OF THE DISCS RECOVERED IN LARVAL INSTAR 3 (L3) INTO TUMORS. Surprisingly, only a brief 24-hour PH depletion was able to trigger tumor formation.
BRIEF KNOCKDOWN OF PH IS SUFFICIENT TO TRIGGER TUMOR FORMATION
The researchers ruled out the presence of other driver genes, genomic instability, and other interferences, and finally determined that the brief depletion of the PRC1 component is sufficient to promote the transformation of normal cells into cancer cells, and even if the PcG concentration is restored, the cancer state will be maintained. The occurrence of this type of cancer is not related to DNA mutations and is entirely determined by epigenetic modifications, which researchers define as epigenetically induced cancers (EICs).
The researchers analyzed the transcriptome of EIC and found that most of the transcriptional defects caused by PH knockdown (75%) recovered with PH levels, but there were still many genes in an "irreversible" state, and they contained a large number of PcG target genes, enriched with genes related to paracrine signaling and cytokine activity, such as multiple ligands of JAK-STAT that have been shown to be associated with cancer.
The researchers analyzed the changes in chromatin accessibility before and after knockdown PH, performed ATAC-Seq on the genome, and found 1220 reversible peaks that significantly increased accessibility after PH depletion but returned to normal levels after PH recovery, and 446 peaks irreversibly increased accessibility with PH depletion.
The researchers found that the STAT92E and ZFH1 motifs were one of the best predictors of increased and decreased accessibility after temporary knockdown of PH, respectively.
STAT92E和ZFH1至关重要
Transcription factor STAT92E is an important component of the JAK-STAT pathway in Drosophila, ZFH1 is a transcriptional repressor activated by STAT92E, and its homolog ZEB1 mutation in humans has been implicated in cancer.
The results showed that neither knockdown STAT92E nor ZFH1 alone affected the occurrence of cancer, and both were required to ensure the driving effect of PH knockdown on cancer.
STAT92E and ZFH1 are required for cancer development
Now we can figure out what happened.
Temporary disruption of PcG-mediated gene silencing irreversibly activates the JAK-STAT pathway, thereby inducing cell proliferation and ZFH1, which inhibits genes required for eye disc development in Drosophila larvae, preventing cell differentiation and leading to EIC formation.
Once JAK-STAT is activated, the subsequent development cannot help but be controlled by PcG. The researchers transplanted the EIC developed by the larvae into the abdomen of an adult Drosophila and found that these EIC continued to grow until the host was killed, and they could maintain amplification activity even after ten rounds of transplantation, and the metastatic penetrance increased with the number of transplants.
The investigators believe that the tumorigenic potential of EIC increases over time may indicate that they have acquired genetic or epigenetic secondary modifications.
This study was conducted in Drosophila larvae with tissues that are in the developmental stage and therefore have high plasticity, and it is unclear whether EIC is also present in more differentiated mature tissues.
However, temporary epigenetic changes are actually quite common in human life, and certain diets and drugs, or exposure to certain chemical agents may cause epigenetic changes, and the discovery of EIC may be of great significance for human cancer research.
Resources:
[1]https://www.nature.com/articles/s41586-024-07328-w
[2]https://www.nature.com/articles/d41586-024-01019-2
The author of this article丨 Dai Siyu