The main focus of our research is to understand how posttranslational modifications—particularly by ubiquitin-related modifiers such as SUMO—of cancer-related factors, regulate cellular process in cancer biology and treatment. Through our research we hope to provide a novel angle of understand 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. We are investigating how HDAC2 regulates cellular processes by promoting substrate sumoylation.

Figure 1. Addition of purified recombinant HDAC2 protein directly stimulates in vitro sumoylation of eukaryotic translation initiation factor 4E (eIF4E).  1 µl of in vitro translated human influenza hemagglutinin (HA) tagged eIF4E was used as SUMO substrate.  0-200 ng of human recombinant HDAC2 protein (Biomol International) was added to the in vitro sumoylation reaction mixture as labeled in the figure.  Sumoylated and non-sumoylated HA-eIF4E were detected by immunoblotting with anti-HA.  Addition of HDAC2 was verified by immunoblotting.

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 new, targeted class of anticancer drugs. Two HDACi, Vorinostat and Romidepsin, are licensed by the United States FDA for the treatment of advanced cutaneous T-cell lymphoma (CTCL). Currently more than 10 HDACi from at least 18 companies are being extensively tested in clinical trials for solid tumors. However, in contrast to their powerful anti-tumor effect in patients with CTCL, HDACi as monotherapy only exhibit limited clinical efficacy against solid tumors.  Developing strategies to overcome this challenge is of great interest to the scientific, pharmaceutical and medical community, and requires our clear understanding of underlying HDAC biology that renders a particular type of tumor refractory to HDACi. Using tissue culture and tumor xenograft models, currently we are testing our hypothesis that HDAC2 mediates refractoriness to HDACi therapy through promoting substrate sumoylation.

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Important Publications

Xu X, J Vatsyayan, C Gao, CJ Bakkenist and J Hu.  HDAC2 promotes eIF4E sumoylation and activates mRNA translation specifically.  J Biol Chem285:18139-18143, 2010.

Xu X, J Vatsyayan, C Rao, CJ Bakkenist and J Hu. Sumoylation of eIF4E activates mRNA translation.  EMBO Reports 11:299-304, 2010.

Vatsyayan J, GL Qing, G Xiao and J Hu.  SUMO-1 modification of NF-?B2/p100 is essential for stimuli-induced p100 phosphorylation and processing.  EMBO Reports 9:885-890, 2008.

Hu J, J Straub, D Xiao, SV Singh, HS Yang, N Sonenberg and J Vatsyayan.  Phenethyl isothiocyanate, a cancer chemopreventive constituent of cruciferous vegetables, inhibits cap-dependent translation by regulating the level and phosphorylation of 4E-BP1.  Cancer Res 67(8):3569-3573, 2007.