HDAC inhibitors augmented cell migration and metastasis through induction of PKCs leading to identification of low toxicity modalities for combination cancer therapy.

PURPOSE: Histone deacetylase inhibitors (HDACi) are actively explored as new-generation epigenetic drugs but have low efficacy in cancer monotherapy. To reveal new mechanism for combination therapy, we show that HDACi induce cell death but simultaneously activate tumor-progressive genes to ruin therapeutic efficacy. Combined treatments to target tumorigenesis and HDACi-activated metastasis with low toxic modalities could develop new strategies for long-term cancer therapy. EXPERIMENTAL DESIGN: Because metastasis is the major cause of cancer mortality, we measured cell migration activity and profiled metastasis-related gene expressions in HDACi-treated cancer cells. We developed low toxic combination modalities targeting tumorigenesis and HDACi-activated metastasis for preclinical therapies in mice. RESULTS: We showed that cell migration activity was dramatically and dose dependently enhanced by various classes of HDACi treatments in 13 of 30 examined human breast, gastric, liver, and lung cancer cell lines. Tumor metastasis was also enhanced in HDACi-treated mice. HDACi treatments activated multiple PKCs and downstream substrates along with upregulated proapoptotic p21. For targeting tumorigenesis and metastasis with immediate clinical impact, we showed that new modalities of HDACi combined drugs with PKC inhibitory agent, curcumin or tamoxifen, not only suppressed HDACi-activated tumor progressive proteins and cell migration in vitro but also inhibited tumor growth and metastasis in vivo. CONCLUSION: Treatments of different structural classes of HDACi simultaneously induced cell death and promoted cell migration and metastasis in multiple cancer cell types. Suppression of HDACi-induced PKCs leads to development of low toxic and long-term therapeutic strategies to potentially treat cancer as a chronic disease.

Androgen receptor is a new potential therapeutic target for the treatment of hepatocellular carcinoma.

BACKGROUND & AIMS: Androgen effects on hepatocellular carcinoma (HCC) remain controversial and androgen ablation therapy to treat HCC also leads to inconsistent results. Here we examine androgen receptor (AR) roles in hepatocarcinogenesis using mice lacking AR in hepatocytes. METHODS: By using the Cre-Lox conditional knockout mice model injected with carcinogen, we examined the AR roles in hepatocarcinogenesis. We also tested the possible roles of AR in cellular oxidative stress and DNA damage sensing/repairing systems. By using AR degrading compound, ASC-J9, or AR-small interference RNA, we also examined the therapeutic potentials of targeting AR in HCC. RESULTS: We found AR expression was increased in human HCC compared with normal livers. We also found mice lacking hepatic AR developed later and less HCC than their wild-type littermates with comparable serum testosterone in both male and female mice. Addition of functional AR in human HCC cells also resulted in the promotion of cell growth in the absence or presence of 5alpha-dihydrotestosterone. Mechanistic dissection suggests that AR may promote hepatocarcinogenesis via increased cellular oxidative stress and DNA damage, as well as suppression of p53-mediated DNA damage sensing/repairing system and cell apoptosis. Targeting AR directly via either AR-small interference RNA or ASC-J9 resulted in suppression of HCC in both ex vivo cell lines and in vivo mice models. CONCLUSIONS: Our data point to AR, but not androgens, as a potential new and better therapeutic target for the battle of HCC.

YY1AP, a novel co-activator of YY1.

With the aim of identifying potential cellular proteins that mediate the transcriptional regulation of YY1, a HeLa cDNA library was screened using the yeast two-hybrid system. A previously unknown protein interacting with YY1 was identified and named YY1AP. By using the 5'-rapid amplification of cDNA ends technique, the full-length cDNA of YY1AP was cloned and sequenced. The cDNA was 2253 bp in length and encoded an open reading frame of 750 amino acids. The chromosomal gene was made up of 10 exons separated by nine introns and is localized on chromosome 1 (1q21.3). Northern blot analysis revealed that YY1AP is ubiquitously expressed in various human tissues and cancer cell lines. Co-immunoprecipitation and immunostaining of cells further indicated that YY1AP co-localizes with YY1 in the nucleus. Furthermore, YY1AP was shown to be capable of enhancing the transcriptional activation of an YY1 responsive promoter. Subsequent analysis by glutathione S-transferase pull-down assay showed that YY1AP contained two YY1 binding regions. The transactivation region of YY1AP would seem to be localized within the section of amino acids 260-345. It is proposed that YY1AP is a novel co-activator of YY1.