The main focus of our research is to understand how posttranslational modifications—particularly phosphorylation, sumoylation and ubiquitination—of cancer-related factors, regulate cellular process in cancer biology and treatment. Through our research we hope to provide a novel angle of understanding why chemotherapy often fails. Our goal is to identify novel molecular targets or events that have potential to guide the clinical development of new means to inhibit tumor progression and chemoresistance.
One of our research aims is to investigate how HDAC2 (Histone deacetylase 2) promotes tumorigenesis through enhancing substrate sumoylation. HDAC2 is a key regulator of oncogenic processes and is elevated in several human cancers, but how HDAC2 functions to promote carcinogenesis remains elusive. A commonly known feature of HDAC is to remove the acetyl group from an acetylated lysine and, consequently, our view of HDAC has for many years been solely from the deacetylase perspective. Intriguingly, we have found that HDAC2 possesses a deacetylase-independent sumoylation-promoting activity. To date we have identified two sumoylation substrates of HDAC2, including eukaryotic initiation factor 4E (eIF4E).
eIF4E is an mRNA
cap-binding factor. As a potent oncogene, eIF4E is found elevated in many human
cancer including colorectal cancer (CRC). High levels of eIF4E contribute to
carcinogenesis by stimulating protein synthesis of cancer-related genes—genes
related to growth, proliferation and apoptosis. We find that sumoylation
activates eIF4E-dependent mRNA translation and is required for eIF4E’s
anti-apoptotic and oncogenic properties. We further show that HDAC2 promotes
sumoylation of eIF4E, resulting in activation of protein translation of a
subset eIF4E-target genes. These findings raise the possibility that HDAC2
promotes tumorigenesis through upregulating sumoylation of eIF4E. We are
currently validating the functional role of HDAC2 sumoylation activity in
intestinal tumorigenesis and dissecting the molecular basis underlying it.
We are also interested in uncovering the HDAC mechanism responsible for the limited efficacy of histone deacetylase inhibitor (HDACi) treatment in solid tumors. HDACi is a promising new class of anticancer drugs. Two HDACis—Vorinostat (SAHA) and Romidepsin—are licensed by the United States FDA for the treatment of advanced cutaneous T-cell lymphoma. Despite its low
clinical efficacy as a single agent, HDACi shows promise in combination therapy
in lung cancer patients suggesting that the full therapeutic potential of
HDACis will probably be best realized through a combination with other
anticancer agents. Currently there are about 10 ongoing clinical trials testing
HDACis for colon cancer (ClinicalTrials.gov); therefore it is critical to
identify resistance mechanisms that can lead to strategies that increase HDACi
therapeutic potential in CRC. We are investigating HDACi resistance from a
previously unexplored angle—HDAC2-mediated sumoylation. We hope the information
gained from this study could lead to identification of new drug combinations
and more rationally designed future trials.
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