Researchers have revealed a previously unappreciated role for a group of proteins called KRAB zinc finger proteins (KZFPs), finding that they can help lymphoma cells avoid immune system detection.
KZFPs are transcription factor proteins which control which genes are switched on or off. Some KZFPs interact with transposable elements (TEs), which make up more than half of the human genome. TEs can cause genomic instability if left unchecked, so KZFPs play a crucial role in repressing TEs and ensuring genomic stability, by packaging TEs into ‘heterochromatin’.
However, some KZFPs are also known to promote disease progression in some cancers. The Swiss team set out to investigate whether the same was the case in diffuse large B cell lymphoma (DLBCL).
In their latest study, they examined the impact of depleting two of these proteins, ZNF587 and ZNF417, in tumour cells from lymphoma and other cancers. Doing so creates replicative stress, triggering an inflammatory response and “unmasking” the cancer cells to the immune system.
They also found that high levels of expression of a group of KZFPs correlates with poor prognosis for DLBCL.
Study leader Didier Trono, of Ecole Polytechnique Federale de Lausanne, said: “Our study shows that TE regulation and heterochromatin maintenance by KZFPs is essential also in cancer, which allowed us to uncover new functions of KZFPs, previously overlooked in cancer research due to their young evolutionary age and presumed redundancy.
“Three-quarters of KZFP genes are primate-restricted, challenging the conventional wisdom that the more conserved a protein is, the more essential it should be for cancer development.
“Our findings indicate that KZFPs not only regulate gene expression but also participate in DNA replication and genome stability, which can influence the genetic diversity and occurrence of subclonal populations of cancer cells, thus playing a pro-oncogenic role.”
Fellow researcher Filipe Martins added: “These phenomena have so far been seen only with chemotherapy agents or depletion of cellular enzymes. Therefore, targeting transcription factors holds the promise of a potential immunogenic chemotherapy-like effect.”
Source:
Martins F, Rosspopoff O, Carlevaro-Fita J, Forey R, Offner S, Planet E, Pulver C, Pak H, Huber F, Michaux J, Bassani-Sternberg M, Turelli P, Trono D. (2024) “A cluster of evolutionarily recent KRAB zinc finger proteins protects cancer cells from replicative stress-induced immunogenic inflammation.” Cancer Research, doi: 10.1158/0008-5472.CAN-23-1237
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