LAUSR

The circadian clock lies in the suprachiasmatic nucleus of the hypothalamus and is regulated directly by the daily light/dark cycles, generating rhythmic expression of core circadian-controlled genes (CCCG) some belonging to the nuclear receptors (NR) superfamily. Recent advances show that the disruption of the circadian clock is identified as a risk factor for endocrine cancers, such as prostate cancer which is the most common hormone-related male cancer globally. Whether the prostate gland has its own circadian expression of CCCG and NR, and how the dysregulated circadian clock would influence the fate of the prostate tumors is not well studied. Thus, the present study aims to determine the circadian expression patterns of CCCG and NR in normal mouse prostate and further validate their disrupted circadian expression in a transgenic mouse adenocarcinoma prostate cancer model (TGMAP) with neuroendocrine phenotypes and suppressed androgen gene expression (AR), over the 12 hours light/dark cycle. We establish the rhythmic expression patterns of multiple CCCG and the full class of NR by quantitative polymerase-chain reaction analysis in normal mouse prostate (C57BL/6 strain) and advanced prostate tumors derived from TGMAP in a 12-hours light/dark cycle with 4-hours interval. Our results showed that 30 out of 49 NR and several CCCG follow rhythmic expression patterns, followed by 10 NR with unidentifiable expression patterns and 9 NR showing very low expression in the mouse prostate tissue. The circadian expression of these transcription factors including the AR gene, could be divided into 2 categories with single peak or double peaks at specific time points throughout the light/dark cycle, linking them to the regulating function of the circadian clock in the normal prostate gland. In the advanced prostate tumors derived from TGMAP model that exhibit androgen independence and neuroendocrine trans-differentiation phenotype, the rhythmic cycles of the NR and CCCG showed disruption, and several transcription factors were upregulated in overall circadian expression in comparison to the normal prostate tissue. In summary, this study establishes two categories of rhythmic expression patterns in normal mouse prostate tissue that link the circadian expression of these transcription factors in the peripheral clock to that of androgen signaling axis that is responsible for the maintenance of prostate gland while disruption of such circadian expression patterns was demonstrated in the TGMAP tumors of which the AR signaling was either lost or disrupted. The upregulated circadian expression patterns as revealed in TGMAP model also provide insight into the significance of the dysregulation of circadian rhythm as regulated by CCCG and NR in the advanced prostate cancer. (Study supported by a Direct Grant for Research 2021-2022 Project No. 2021.062, CUHK) Citation Format: Ria Chopra, Franky Leung Chan. An expression study of circadian clock-associated transcription factors and nuclear receptors in mouse prostate gland and tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1456.