A single protein affects susceptibility of cancer cells to chemotherapy

A newly discovered weakness in cancer cells may make them more susceptible to chemotherapy and other treatments. The HDAC5 protein has been identified as essential for the maintenance of telomeres, which are structures within cancer cells that promote their longevity.

Cancer cells with longer telomeres tend to be more resistant to therapies, and those with shorter telomeres tend to be more susceptible. By targeting the mechanism used by cancer cells to maintain telomeres, existing therapies could become far more effective at eradicating cancer than they are today. That mechanism has been found to be HDAC5.

"Our study can contribute to the development of new combined anticancer therapies," said Denis Mottet, PhD, a researcher involved in the work from the University of Liege Sart-Tilman, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-Cancer, Metastasis Research Laboratory, in Liege, Belgium. "By maintaining a reduced telomere length via HDAC5 inhibition, cancer cells are more sensitive to chemotherapeutic drugs."

To make this discovery, Mottet and colleagues analyzed several cancer cell lines with different backgrounds regarding their telomere biology, including different telomere lengths and different molecular mechanisms to maintain telomere length. They found that HDAC5 co-localized with telomeres only in cancer cells with very long telomere lengths.

Researchers then depleted this HDAC5 protein in cancer cells with varied telomere lengths and observed that telomeres were shortened exclusively in cancer cells that originally had longer telomeres. Cells with shorter telomeres did not seem to be affected by the absence of the HDAC5 protein.

The researchers also found that some cancer cells with very long telomeres were resistant to death induced by common chemotherapy drugs, but the reduction of HDAC5 protein levels in these cells and the subsequent telomere shortening sensitized the cells to these agents, leading to massive cell death. Since telomere shortening also is directly linked to cell aging, premature aging syndromes, and advanced aging diseases, this research could eventually have widespread clinical impact.

"The 'cure for cancer' may not come from a single discovery, but will surely arrive step-by-step. This study defines one of those steps," said Gerald Weissmann, MD, Editor-in-Chief of The FASEB Journal, where this study was published (2013; doi:10.1096/fj.12-224204). "What these scientists have done is to accelerate the aging of cancer cells, so as to weaken them enough to be killed by anti-cancer drugs. This type of discovery was unfathomable when Nixon first declared war on the disease in 1971."
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