A new epigenetic target
for treating all cancers

What doesn’t kill you makes you stronger. This slogan for personal resilience is unfortunately the motto by which cancer cells exist. Reduced oxygen, which usually prompts cells to die, makes tumor cells harder to destroy and more resistant to cancer treatments. However, investigators at the Nanyang Technological University in Singapore recently reported in the journal Molecular & Cellular Proteomics a promising drug target that could stop the tumor before it builds its strength.

In the early stage of cancer, the tumor grows faster than blood vessels can, reaching a point at which it becomes deprived of oxygen, or hypoxic. To sustain itself, the tumor takes on new physical characteristics and acquires improved survival and self-renewal capabilities. Attacking the tumor at this advanced stage becomes challenging because of its diverse traits and enhanced hardiness. However, tumors of all cancer types have to go through the initial hypoxic stage, so drugs targeting the proteins responsible for the hypoxia-induced evolution could be used for a wide range of cancers.

Gene expression requires not only the direct translation of the DNA into proteins but also physical alterations to the structure of the chromatin to allow for the transcription. Several studies have ascribed the changes in gene expression of cancer cells to chromatin-structure modifications. Many have investigated the role of transcription factors called hypoxia-inducible factors in controlling these epigenetic changes. However, hypoxia can induce changes outside of hypoxia-inducible factors, motivating the researchers led by Siu Kwan Sze to investigate the role of HP1BP3, or heterochromatin protein 1, binding protein 3, a novel chromatin-organizing protein they had previously discovered to be important in chromatin condensation and gene-transcription regulation.

HP1BP3-deficient cells (right) formed smaller tumor spheres than HP1BP3-present cells (left) in hypoxia.

The investigators subjected A431 squamous cancer cells, a cell line commonly used to study tumor progression, to three oxygen-level conditions that reflected the phases of a tumor’s development. Normoxic, normal oxygen level, represented the phase during which the single cancer cells proliferate into a tumor. Hypoxic corresponded to the point at which the tumor has outgrown the surrounding blood vessel network. Hypoxic followed by normoxic simulated the late stage, when the tumor evolves to sustain itself. The researchers used quantitative proteomic techniques to identify which chromatin-bound proteins changed with the oxygen conditions. They found high amounts of HP1BP3 in the condensed chromatin from cells exposed to hypoxia compared with those in normoxic conditions. They also observed that hypoxic cells had more condensed chromatin than normoxic cells. Their data supported that HP1BP3 was sensitive to oxygen level and that the chromatin compacting that occurred with hypoxia could be mediated by the protein.

The investigators next removed HP1BP3 from the cells to identify the downstream genes that the protein affected. They reported that fewer HP1BP3-deficient cells survived when exposed to hypoxia, radiation and chemotherapy drugs compared with HP1BP3-present cells. HP1BP3-deficient cells also formed smaller tumors, indicating that these cells had reduced renewal capacity. The data supported that HP1BP3 regulated genes that conferred self-proliferation and increased survival.

The authors conclude that hypoxia influences HP1BP3’s interaction with the chromatin to promote condensation. This change shifts the genes expressed to favor traits that promote cell vitality. Depleting HP1BP3, then, could diminish the tumor’s progression and increase the tumor’s sensitivity to cancer treatments, killing the tumor at the hypoxic stage before it becomes stronger.

Maggie Kuo Maggie Kuo (mkuo@asbmb.org) is an intern at ASBMB Today and a Ph.D. candidate in biomedical engineering at Johns Hopkins University.