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Summary Tumor associated macrophages (TAM) contribute to all aspects of tumor progression. Use of CSF1R inhibitors to target TAM is therapeutically appealing, but has had very limited antitumor effects. Here, we have identified the mechanism that limited the effect of CSF1R targeted therapy. We demonstrated that carcinoma associated fibroblasts (CAF) are major sources of chemokines that recruit granulocytes to tumors. CSF1 produced by tumor cells caused HDAC2-mediated down-regulation of granulocyte-specific chemokine expression in CAF, which limited migration of these cells to tumors. Treatment with CSF1R inhibitors disrupted this cross talk and triggered a profound increase in granulocyte recruitment to tumors. Combining CSF1R inhibitor with a CXCR2 antagonist blocked granulocyte infiltration of tumors and showed strong anti-tumor effects.

Extracts of the resin of the guggul tree (Commiphora mukul) lower LDL (low-density lipoprotein) cholesterol levels in humans. The plant sterol guggulsterone [4,17(20)-pregnadiene-3,16-dione] is the active agent in this extract. We show that guggulsterone is a highly efficacious antagonist of the farnesoid X receptor (FXR), a nuclear hormone receptor that is activated by bile acids. Guggulsterone treatment decreases hepatic cholesterol in wild-type mice fed a high-cholesterol diet but is not effective in FXR-null mice. Thus, we propose that inhibition of FXR activation is the basis for the cholesterol-lowering activity of guggulsterone. Other natural products with specific biologic effects may modulate the activity of FXR or other relatively promiscuous nuclear hormone receptors.

A yeast two-hybrid screen using the conserved carboxyl terminus of the nuclear receptor corepressor SMRT as a bait led to the isolation of a novel human gene termed SHARP (SMRT/HDAC1 Associated Repressor Protein). SHARP is a potent transcriptional repressor whose repression domain (RD) interacts directly with SMRT and at least five members of the NuRD complex including HDAC1 and HDAC2. In addition, SHARP binds to the steroid receptor RNA coactivator SRA via an intrinsic RNA binding domain and suppresses SRA-potentiated steroid receptor transcription activity. Accordingly, SHARP has the capacity to modulate both liganded and nonliganded nuclear receptors. Surprisingly, the expression of SHARP is itself steroid inducible, suggesting a simple feedback mechanism for attenuation of the hormonal response. The transcription action of steroids, retinoids, and thyroid hormone and their cognate receptors (NRs) (Mangelsdorf and Evans 1995; are modulated by an extensive set of nuclear receptor cofactors Glass and Rosenfeld 2000;Westin et al. 2000). A great deal of effort has focused on the identification and characterization of the constituents of these complexes to understand the mechanistic basis of the regulated events. The recruitment of coactivator complexes is a critical step in hormone induction, whereas the recruitment of corepressor complexes mediates active repression of unliganded nuclear receptors. SMRT and N-CoR have been identified as nuclear receptor corepressors (Chen and Evans 1995;Horlein et al. 1995;Ordentlich et al. 1999). Various lines of evidence suggest that at least one mechanism underlying the repression activity of SMRT and N-CoR is through their recruitment of a histone deacetylase complex containing mSin3A and HDAC1 (Alland et al. 1997;Hassig et al. 1997;Heinzel et al. 1997;Laherty et al. 1997;Nagy et al. 1997;Zhang et al. 1997). Direct interaction of SMRT with the class II histone deacetylase (HDAC 4-7) independent of Sin3A provides yet another mechanism for SMRT-mediated transcriptional repression (Huang et al. 2000;Kao et al. 2000). Recruitment of histone deacetylase complexes by corepressors has been proposed to cause a local change in the chromatin structure, therefore resulting in transcriptional repression (Knoepfler and Eisenman 1999).A search for cofactors that mediate ligand-dependent transactivation by nuclear receptors led to the identification of coactivators such as CBP/p300, PCAF, and the p160 family members including SRC-1, GRIP1/TIF2, and ACTR/RAC3/p/CIP (Onate et al. 1995;Hong et al. 1996; Kamei et al. 1996;Yao et al. 1996;Chen et al. 1997;Torchia et al. 1997;Blanco et al. 1998). Among these factors, CBP, PCAF, SRC-1, and ACTR have been shown to possess intrinsic histone acetyltransferase activity, consistent with a role for induced histone acetylation in transcriptional activation (Bannister and Kouzarides 1996;Ogryzko et al. 1996;Yang et al. 1996;Chen et al. 1997;Spencer et al. 1997). Targeted deletion of SRC-1 or p/CIP causes partial hormone insensitivity, suggesting a criti...

Histone deacetylase inhibitors (HDACI) are promising antitumor agents. Although transcriptional deregulation is thought to be the main mechanism underlying their therapeutic effects, the exact mechanism and targets by which HDACIs achieve their antitumor effects remain poorly understood. It is not known whether any of the HDAC members support robust tumor growth. In this report, we show that HDAC6, a cytoplasmic-localized and cytoskeletonassociated deacetylase, is required for efficient oncogenic transformation and tumor formation. We found that HDAC6 expression is induced upon oncogenic Ras transformation. Fibroblasts deficient in HDAC6 are more resistant to both oncogenic Ras and ErbB2-dependent transformation, indicating a critical role for HDAC6 in oncogene-induced transformation. Supporting this hypothesis, inactivation of HDAC6 in several cancer cell lines reduces anchorage-independent growth and the ability to form tumors in mice. The loss of anchorage-independent growth is associated with increased anoikis and defects in AKT and extracellular signal-regulated kinase activation upon loss of adhesion. Lastly, HDAC6-null mice are more resistant to chemical carcinogen-induced skin tumors. Our results provide the first experimental evidence that a specific HDAC member is required for efficient oncogenic transformation and indicate that HDAC6 is an important component underlying the antitumor effects of HDACIs. [Cancer Res 2008;68(18):7561-9]