Heterochromatin loss and genetic instability play a role in cancer progression by promoting clonal diversity. However, excessive replication stress can lead to a mito-** catastrophe and trigger an inflammatory response, which in turn leads to immune rejection of cancer cells.
The KRAB domain-containing zinc finger protein (KZFP) contributes to the stability of the genome by helping to maintain heterochromatin at the transposable element (TE).
In a new study, EPFL scientists identified a panel of primate-specific KZFPs as being associated with poor prognosis, increased copy number changes, and changes in the tumor microenvironment in diffuse large B-cell lymphoma (DLBCL). They have revealed how cancer cells can use certain proteins to protect themselves from immune attack, opening up new prospects for immediate applications.
The study, led by EPFL's Trono group, uncovered an important strategy for cancer cell use. In particular, scientists have identified a group of proteins known as "KRAB zinc finger proteins" (KZFPS). These proteins help cancer cells manage genetic stability and avoid immune system testing.
KZFP acts as a watchdog within our cells, controlling which parts of our DNA are active or inactive. Some KZFPs specifically target repetitive DNA sequences called transposable elements (TEs), which make up a large portion of our genome. If TEs become active, they can cause genetic instability, threatening the health of the cells and immune detection. KZFP helps to silence TE in heterochromatin, a tightly packed DNA structure, thus preserving the stability of our genome.
In a recent study led by Martins, a scientist at Trono's team, researchers found a link between certain primary-specific KZFPs and the prognosis of diffuse large B-cell lymphoma (DLBCL) of the cancer type. Using advanced cell culture techniques and genetic manipulation methods, they investigated the effects of reducing two specific KZFPs in various cancer tumor cells, including DLBCL.
Scientists have focused on two proteins, ZNF587 and ZNF417, because they are associated with a poor prognosis in diffuse large B-cell lymphoma (DLBCL). These proteins also target newer transposable elements in our DNA that have been implicated in maintaining genome stability and helping cancer cells evade the immune system.
When ZNF587 and ZNF417 are removed from DLBCL cells, it causes significant interference with the function of the cells. Their deletion results in a change in the distribution of heterochromatin, a tightly packed DNA structure. This change leads to replication stress, slowing or stopping DNA replication and cell**.
This stress triggers an inflammatory response that makes cancer cells more visible to the immune system. In the absence of ZNF587 and ZNF417, cancer cells show a more diverse variety of neoantigens that alert the immune system to attack them.
"Our study shows that the regulation of TE by KZFPS and the maintenance of heterochromatin are also critical in cancer, allowing us to uncover new functions in KZFPS, which was previously overlooked in cancer research due to its young evolutionary age and presumed redundancy," Trono said. Three-quarters of the KZFP genes are primary-restricted, challenging the conventional wisdom that the more conservative the protein, the more important it is for cancer development. Our findings suggest that KZFP regulates gene expression and is involved in DNA replication and genome stability, which affects the genetic diversity and occurrence of cancer cell subclonal populations, thereby exerting a pro-cancer effect. ”
Martins added: "This DNA damage and 'viral mimicry' of Te leads to the activation of intracellular inflammatory pathways due to its upregulation, thereby contributing to immune rejection in vitro." So far, these phenomena have only occurred in the case of depletion of chemotherapy drugs or cellular enzymes. Therefore, targeting transcription factors is expected to produce potential immunogenic chemotherapy-like effects. The findings suggest that cancer cells may use these proteins to modulate their visibility to immune surveillance. This is a real conceptual breakthrough. Most transposable elements, which are only thought to be genetic threats, have been found to be sentinels against the loss of epigenetic control, and their KZFPS regulators are destroyed by cancer cells to evade this surveillance. ”
This discovery also highlights a potential new target for diffuse large B-cell lymphoma. This discovery immediately points to a new avenue for the disease.