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FRIPRO-Fri prosjektstøtte

Actin acetylation in cancer metastasis: a tale of a forgotten tumor suppressor

Alternative title: Protein acetylering og kreftmetastasering

Awarded: NOK 12.5 mill.

All aspects of the life of a human cell are controlled by proteins. Proteins can be modified by different chemical groups functioning as tags controlling protein function. One particular chemical group, acetyl, is coupled to nearly every single protein in our cells. Our research group at UiB has defined the entire machinery in human cells attaching this tag to the end (N-terminal end) of proteins. The enzymes doing this job are called NAT-enzymes. Surprisingly, we do not yet understand why most proteins are acetylated, but in recent years researchers have shown that the acetyl-tags may control the stability and trafficking of proteins. In any case, it is becoming clear that the acetylation of proteins is a process of crucial importance for humans. Recently, we discovered a novel NAT enzyme in human cells which adds an acetyl-tag to a protein controlling the structure of the cell. Removal of this NAT and thereby the protein acetylation, changed the cytoskeleton and the ability of the cell to migrate. Earlier it was observed that the gene encoding this NAT may be disrupted in certain types of cancer with a strong metastatic potential. In this project, we will define the mechanisms for protein acetylation mediated control of the cytoskeleton and cell migration and investigate if this may impact the ability of cancer cells to metastasize.

Forty years ago, a specific part of chromosome 3 was found to be deleted in most patients with small cell lung cancer (SCLC), which is the most aggressive form of lung cancer due to its metastatic capacity. Therefore, it was thought that this DNA region harboured one or more tumour suppressor genes. After many years of investigations focusing on the core genes in this region, there is still no understanding of how lung cancer cells are affected by lacking this part of the chromosome. Other genetic changes in lung cancer that could explain rapid cell division and survival were found elsewhere in the genome, but SCLC's strong metastatic capacity remains enigmatic. One of the genes of unknown function in the border of the DNA region missing in SCLC is NAA80. We recently revealed that NAA80 acetylates actin and that cancer cells lacking NAA80 has a completely altered cytoskeleton and a drastically increased motility. This knowledge prompted us to hypothesize that defective NAA80 and impaired actin acetylation could be a driver for SCLC metastasis. Preliminary investigations in SCLC cell lines uncovered that NAA80 may be homozygously deleted or otherwise mutated and that actin acetylation is correspondingly reduced. Of note, in SCLC cells, we found a correlation between lack of NAA80 and increased cytoskeletal protrusions and motility rate. Further, reintroduction of NAA80 in NAA80-lacking SCLC cells reduced such motility-promoting cytoskeletal protrusions. In the ActInCancer project we will define the role of NAA80 and actin acetylation in SCLC metastasis. We will use a panel of SCLC cell lines, a collection of patient tissues and orthotopic mouse models, combined with state-of-the-art imaging, proteomics, biochemistry and cell biology. This may provide a long-sought mechanistic understanding of metastasis in a subgroup of SCLC patients and represent an important starting-point for new SCLC treatments.

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FRIPRO-Fri prosjektstøtte

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