Dissecting the Regulation of c-Myc by HDAC6 and Its Role in the Anticancer Activity of HDAC6 Inhibitors
Abstract
Recently, we reported that the viability of some breast cancer cells depends on the function of histone deacetylase 6 (HDAC6). We also developed an algorithm (HDAC6-score) based on mRNA expression profiling to easily identify cancers with high HDAC6 activity that depend on HDAC6 function. By analyzing over 3,000 primary breast cancers, we found that ~30% of all breast cancers can benefit from targeted therapy against HDAC6. Small-molecule inhibitors for HDAC6 (HDAC6i) already exist and are currently being tested in advanced clinical trials. Our previous studies revealed that the clinical benefit rate (CBR) of the regiment containing Ricolinostat/ACY1215 almost doubled that in the chemotherapy-only control cohort, 31% vs. 19%. Understanding the molecular mechanism that mediates the activity of anticancer agents is critical to obtain the best therapeutic outcomes. In this regard, one of the most important findings of our research has been the identification of c-Myc as a substrate of HDAC6. c-Myc is one of the major human cancer oncogenes and it is well-known that a large variety of cancers depend on c-Myc expression to proliferate. In fact, c-Myc has been historically seen as a bonafide cancer target. Unfortunately, therapeutic strategies aimed to inhibit c-Myc have found multiple roadblocks and their translation to the clinic is still anecdotic. Thus, investigating how c-Myc expression is controlled by HDAC6 represents a unique opportunity that can lead to the generation of efficient, targeted therapies to downregulate c-Myc utilizing HDAC6 inhibitors. This will not only influence the treatment of breast malignancies but the myriad of Myc-dependent human cancers. In this proposal, our main goals are to dissect the biochemical regulation of c-Myc by HDAC6 and its role in the lethality induced by HDAC6i in cancer cells.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210799
Entities
People
- Jose Silva
Organizations
- Icahn School of Medicine at Mount Sinai
- United States Army