Transcriptional regulation of type 11 17β-hydroxysteroid dehydrogenase expression in prostate cancer cells

Abstract

Type 11 Hydroxysteroid (17-beta) dehydrogenase (HSD17B11) catalyzes the conversion of 5α-androstan-3α,17β-diol into androsterone suggesting that it may play an important role in androgen metabolism. We previously described that overexpression of C/EBPα or C/EBPβ induced HSD17B11 expression in HepG2 cells but this process was not mediated by the CCAAT boxes located within its proximal promoter region. Here, we study HSD17B11 transcriptional regulation in prostate cancer (PC) cells. Transfection experiments showed that the region −107/+18 is sufficient for promoter activity in PC cells. Mutagenesis analysis indicated that Sp1 and C/EBP binding sites found in this region are essential for promoter activity. Additional experiments demonstrated that ectopic expression of Sp1 and C/EBPα upregulated HSD17B11 expression only in PC cell lines. Through DAPA and ChIP assays, specific recruitment of Sp1 and C/EBPα to the HSD17B11 promoter was detected. These results show that HSD17B11 transcription in PC cells is regulated by Sp1 and C/EBPα.

Integrated, High-Throughput, Multiomics Platform Enables Data-Driven Construction of Cellular Responses and Reveals Global Drug Mechanisms of Action

“…Figure E demonstrates a network of events derived de novo from measured molecular changes that potentially lead to resistance through mTOR activation. In cisplatin-treated cells, estrogen species transiently increased: E 1 increased at 1 h, and both E 1 and E 2 increased at 6 h but decreased by 24 h. HSD17β7 increased at 1 h and decreased at 6 h. The transcription factor C/EBPβ, which is activated by cyclic AMP (cAMP)-dependent protein kinase A (PKA), regulates HSD17β dehydrogenase family members . At 24 h, we observed an increase in PKA and in HSD17β7 transcript.…”

“…In cisplatin-treated cells, estrogen species transiently increased: E 1 increased at 1 h, and both E 1 and E 2 increased at 6 h but decreased by 24 h. HSD17β7 increased at 1 h and decreased at 6 h. The transcription factor C/EBPβ, which is activated by cyclic AMP (cAMP)-dependent protein kinase A (PKA), 38 regulates HSD17β dehydrogenase family members. 39 At 24 h, we observed an increase in PKA and in HSD17β7 transcript. E 2 binds to ESR1 and induces PKCmediated ERK phosphorylation and ERK-dependent mTOR activation.…”

Primary Tumor Site Specificity is Preserved in Patient-Derived Tumor Xenograft Models

“…Four genes, namely, HSD17B11 , ITGA2 , VIM , and ABHD17C , are involved in these rules. The low expression of HSD17B11 and ITGA2 and the high expression of VIM and ABHD17C have all been validated by recent sequencing studies on breast cancer (Rotinen et al, 2011), reflecting the accuracy of these two rules.…”

“…HSD17B11 , encoding short-chain alcohol dehydrogenases, has been widely reported to participate in androgen metabolism during steroidogenesis (Rotinen et al, 2011). As for its contribution on tumorigenesis and specific role during PDX implantation, this gene has only been identified in both primary and implanted tumor tissue of the prostate (Hilborn et al, 2017) and breast tumorigenesis (Rotinen et al, 2011), implying that such gene may distinguish different tumor tissues.…”

A novel prognostic model for prostate cancer based on androgen biosynthetic and catabolic pathways

“…In contrast, SRD5A3 is involved in the production of the androgen 5-alpha-dihydrotestosterone (DHT) from testosterone and maintains the androgen and androgen receptor activation pathway ( 19 ). HSD17B11, MED1, and SPP1 are involved in androgen synthesis and AR receptor activation ( 20 – 22 ). This suggests that in cluster2, androgen synthesis and AR receptor activation may be more active.…”