Epigenetics has moved into the driver’s seat. In a first-of-its-kind study, a talented team show that knocking down polycomb group proteins in Drosophila causes tumors to form, and bringing the proteins back doesn’t fix it. The finding demonstrates that transient epigenetic changes can irreversibly drive cancer—without genetic mutations.
Although we’ve suspected that epigenetic mechanisms could take the wheel, no one had shown it for sure. So, Anne-Marie Martinez and Giacomo Cavalli’s labs at CNRS (France), with collaborators at various institutions, shifted their experiments into high gear using polycomb proteins. These proteins repress developmental genes, and their dysregulation is associated with cancer. The polycomb repressive complex (PRC) 1 contains a PH subunit and deposits H2AK118UB, whereas PRC2 lays down the repressive H3K27me3. With a thermosensitive ph-RNAi system, the teams reversibly knocked down (KD) the PH protein in larval eye imaginal discs. Here’s what they found:
- With constant PH removal, the eye discs develops tumors
- When larvae are exposed to high temperature to remove PH and then returned to normal conditions, the tumors are stable, even though PH levels take a U-turn and bounce back
- Replication is abnormal throughout eye disc tissue early on in transient-KD larvae, making it unlikely that tumors are a result of mutations in a subset of cells
- After sequencing genomic DNA, transient-KD flies’ genes are pretty similar to the controls’ DNA
- Transient depletion doesn’t cause overall genetic instability because the cells can still repair DNA breaks caused by irradiation
Because the same genes resulted in different phenotypes depending on their epigenetic states, the team called the phenomenon “epigenetically initiated cancers” (EICs). Looking into this further, they found:
- When PH levels are brought back to normal, an “irreversible” cluster of differentially expressed genes are still upregulated, including JAK-STAT ligands, as well as zfh1, which act downstream of JAK-STAT and have a mammalian homologue, ZEB1
- Chromatin modifications are re-established for most genes with the transient PH knockdown, but some genes—like zhf1—retain slightly higher levels of H3K27Ac than the control
- AP1 and STAT92E can help maintain irreversible genes in an active, open state at cis-regulatory regions
- Knocking down either STAT92E or ZFH1 with temperature-sensitive KD constructs has no effect, but knocking both down at the same time reduces tumor growth
- EICs are maintained autonomously and can propagate, even after the RNAi that knocked down PH was gone
Overall, the team proposes a multistep model in which transient PH knockdown activates the JAK-STAT pathway, which causes cell proliferation and zfh1 to be induced. ZFH1 then puts the brakes on eye disc development genes so that the discs cannot differentiate.
To check out the details for yourself, hit the gas and accelerate over to Nature, April 2024.