Cell senescence a double-edged sword in cancer treatment


Cell senescence, a state in which cells are unable to divide, has been considered a way to block cancer progression, but Wistar Institute scientists have found that it can also cause side effects that benefit tumors. Manipulating the levels of a certain protein may lead to methods to promote the benefits of senescence while tamping down on its negative effects.

The Wistar team zeroed in on a protein, chromatin, that contributes to the expression of cytokines and chemokines, which are potentially harmful secreted factors, according to a statement. During senescence, some chromatin is reorganized into a new form, known as SAHF, that shuts down genes that drive tumor cell proliferation, but also increases the expression of cytokine and chemokine genes.

"When senescence happens, you have two closely linked phenomena occurring, yet one of these helps to halt tumor progression while the other causes an increase in potentially harmful inflammatory cytokines and chemokines," said Rugang Zhang, lead author of the study and a professor and co-program leader of the Gene Expression and Regulation program at Wistar, in the statement. "We pinpointed the architecture of chromatin and the proteins that influence chromatin organization as the proper place to start to try and solve this paradox."

To address this, the team studied a group of proteins dubbed high mobility group proteins. This set of proteins changes the structure of chromatin to regulate gene transcription. Specifically, the researchers inhibited the high mobility group protein HMGB2, which binds to DNA to increase chromatin’s access to transcription factors, according to the statement. They found that blocking HMGB2 allowed SAHF to successfully “silence” cytokine and chemokine genes, pointing to HMGB2 inhibition as a potential method to suppress the negative effects of senescence.

"Understanding senescence is critical for understanding how tumor growth can be successfully suppressed," said Katherine Aird, a staff scientist in the Zhang lab and first author of the study, in the statement. "With the information from this study, we may be able to increase the effectiveness of chemotherapeutic agents that are able to induce senescence by silencing HMGB2 and decreasing the expression of unwanted secreted factors."