Background: HIF1␣ is a target of anticancer therapy. Results: Lysines within the HIF1␣ N terminus are targets of HDAC4 deacetylation. HDAC4 inhibition causes the increase of HIF1␣ protein acetylation and decrease of protein stability, which lead to the reduction of HIF-1-mediated target gene expressions and activities in cancer cells. Conclusion: HDAC4 provides a novel HIF1␣ regulatory mechanism. Significance: HIF-1 can be targeted by HDAC4 inhibition.

Background-Metastatic prostate cancer is either inherently resistant to chemotherapy or rapidly acquires this phenotype after chemotherapy exposure. In this study, we identified a docetaxel-induced resistance mechanism centered on CCL2.

Highlights d Stepwise model of early to late gilteritinib resistance recapitulates human disease d Early resistant cells in marrow microenvironment rely on AURKB to resume growth d Pre-existing NRAS mutations expand in late resistance and drive relapse d Metabolic reprogramming occurs during evolution of gilteritinib resistance

1,25-Dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ], the most active metabolite of vitamin D 3 , has significant antitumor activity in a broad range of preclinical models of cancer. In this study, we show that the Iroquois homeobox gene 5 (Irx5) is down-regulated by 1,25(OH) 2 D 3 in human prostate cancer samples from patients randomly assigned to receive weekly high-dose 1,25(OH) 2 D 3 or placebo before radical prostatectomy. Down-regulation of Irx5 by 1,25(OH) 2 D 3 was also shown in the human androgen-sensitive prostate cancer cell line LNCaP and in estrogen-sensitive MCF-7 breast cancer cells. Knockdown of Irx5 by RNA interference showed a significant reduction in LNCaP cell viability, which was accompanied by an increase in p21 protein expression, G 2 -M arrest, and an increase in apoptosis. The induced apoptosis was partially mediated by p53, and p53 protein expression was increased as a result of Irx5 knockdown. Cell survival was similarly reduced by Irx5 knockdown in the colon cancer cell line HCT 116 and in MCF-7 breast cancer cells, each being derived from clinical tumor types that seem to be inhibited by 1,25(OH) 2 D 3 . Overexpression of Irx5 led to a reduction of p21and p53 expression. This is the first report that Irx5 is regulated by1,25(OH) 2 D 3 in humans and the first report to show that Irx5 is involved in the regulation of both the cell cycle and apoptosis in human prostate cancer cells. Irx5 may be a promising new therapeutic target in cancer treatment.

To identify potential mechanisms underlying prostate cancer chemotherapy response and resistance, we compared the gene expression profiles in high-risk human prostate cancer specimens before and after neoadjuvant chemotherapy and radical prostatectomy. Among the molecular signatures associated with chemotherapy, transcripts encoding inhibitor of DNA binding 1 (ID1) were significantly upregulated. The patient biochemical relapse status was monitored in a long-term follow-up. Patients with ID1 upregulation were found to be associated with longer relapse-free survival than patients without ID1 increase. This in vivo clinical association was mechanistically investigated. The chemotherapy-induced ID1 upregulation was recapitulated in the prostate cancer cell line LNCaP. Docetaxel dose-dependently induced ID1 transcription, which was mediated by ID1 promoter E-box chromatin modification and c-Myc binding. Stable ID1 overexpression in LNCaP increased cell proliferation, promoted G 1 cell cycle progression, and enhanced docetaxel-induced cytotoxicity. These changes were accompanied by a decrease in cellular mitochondria content, an increase in BCL2 phosphorylation at serine 70, caspase-3 activation, and poly(ADP-ribose) polymerase cleavage. In contrast, ID1 siRNA in the LNCaP and C42B cell lines reduced cell proliferation and decreased docetaxel-induced cytotoxicity by inhibiting cell death. ID1-mediated chemosensitivity enhancement was in part due to ID1 suppression of p21. Overexpression of p21 in LNCaP-ID1-overexpressing cells restored the p21 level and reversed ID1-enhanced chemosensitivity. These molecular data provide a mechanistic rationale for the observed in vivo clinical association between ID1 upregulation and relapse-free survival. Taken together, it shows that ID1 expression has a novel therapeutic role in prostate cancer chemotherapy and prognosis.