Connor Dolan

Background: 90% of prostate cancers are adenocarcinomas. These tumors start in the prostate, with an incidence of 299,010 per year in the United States.¹ Neuroendocrine prostate cancer (NEPC) is a form of prostate cancer, where the tumors are identified as having distinct neuroendocrine biomarkers whilst also having characteristics of prostate cancers.² 25% of the yearly 34,000 cases of death resulting from prostate cancer are due to NEPC.² While the 5-year survival rate of prostate cancer is relatively high, NEPC is marked as having a 10% 5-year survival rate and a median survival after diagnosis of 7 months.^1,2,3

Research Objectives: In this review, we survey research related to the role of FOXA2 in neuroendocrine prostate cancer.

Methods: A PubMed database search was performed for articles published in the last 5 years with the keywords: “Neuroendocrine prostate cancer,” “NEPC,” “FOXA2 Neuroendocrine prostate cancer,” and “Kit Neuroendocrine prostate cancer.”

Results: NEPC can arise de novo or through transdifferentiation from prostate adenocarcinoma (ADPC). The former pathway accounts for 1-2% of all NEPC diagnoses, whereas the latter accounts for the rest of NEPC diagnoses.⁴ NEPC’s transdifferentiation process has two phases: an early phase and a late phase. Noticeably, the FOXA2 transcription factor is seen in both the early phase and late phase of transdifferentiation.² FOXA2 changes chromatin structure to recruit more transcription factors, including Sox10 and MyoG – both indicated in nerve development. FOXA2 upregulates Kit, a gene involved in intracellular signaling that enables the growth, proliferation, and differentiation of NEPC tumors.⁵ In research, FOXA2 is caused by androgen deprivation therapy and as resulting from upregulation of the PHF8 gene.^5,6 While it was unclear in studies what caused the upregulation of the gene, PHF8 demethylates and removes suppressing histone markers around the promoter region of the FOXA2 gene.⁶

Conclusion: While it does not encapsulate the entirety of transdifferentiation, it appears that there is a PHF8-FOXA2 axis that results in Kit, Sox10, and MyoG (among other transcription factors) that are necessary for NEPC. Through unknown mechanisms, PHF8 leads to an upregulation of FOXA2, which leads to the upregulation of the aforementioned transcription factors. There are currently no clinical studies to understand the efficacy of using these biomarkers as potential diagnostic or treatment mechanisms. Future therapeutic studies should initially focus on therapies targeting the FOXA2-Kit pathway, followed by factors associated with PHF8.

Works Cited:

1. Yamada Y, Beltran H. Clinical and Biological Features of Neuroendocrine Prostate Cancer. Curr Oncol Rep. 2021 Jan 12;23(2):15. doi: 10.1007/s11912-020-01003-9. PMID: 33433737; PMCID: PMC7990389.
2. Wang Z, Wang T, Hong D, Dong B, Wang Y, Huang H, Zhang W, Lian B, Ji B, Shi H, Qu M, Gao X, Li D, Collins C, Wei G, Xu C, Lee HJ, Huang J, Li J. Single-cell transcriptional regulation and genetic evolution of neuroendocrine prostate cancer. iScience. 2022 Jun 13;25(7):104576. doi: 10.1016/j.isci.2022.104576. PMID: 35789834; PMCID: PMC9250006.
3. Maleki Z, Nadella A, Nadella M, Patel G, Patel S, Kholová I. INSM1, a Novel Biomarker for Detection of Neuroendocrine Neoplasms: Cytopathologists’ View. Diagnostics (Basel). 2021 Nov 23;11(12):2172. doi: 10.3390/diagnostics11122172. PMID: 34943408; PMCID: PMC8700458.
4. Okasho K, Mizuno K, Fukui T, Lin YY, Kamiyama Y, Sunada T, Li X, Kimura H, Sumiyoshi T, Goto T, Kobayashi T, Lin D, Wang Y, Collins CC, Inoue T, Ogawa O, Akamatsu S. Establishment and characterization of a novel treatment-related neuroendocrine prostate cancer cell line KUCaP13. Cancer Sci. 2021 Jul;112(7):2781-2791. doi: 10.1111/cas.14935. Epub 2021 Jun 1. PMID: 33960594; PMCID: PMC8253279.
5. Ming Han, Fei Li, Yehan Zhang, Pengfei Dai, Juan He, Yunguang Li, Yiqin Zhu, Junke Zheng, Hai Huang, Fan Bai, Dong Gao, FOXA2 drives lineage plasticity and KIT pathway activation in neuroendocrine prostate cancer, Cancer Cell, Volume 40, Issue 11, 2022, Pages 1306-1323.e8, ISSN 1535-6108
6. Liu Q, Pang J, Wang LA, Huang Z, Xu J, Yang X, Xie Q, Huang Y, Tang T, Tong D, Liu G, Wang L, Zhang D, Ma Q, Xiao H, Lan W, Qin J, Jiang J. Histone demethylase PHF8 drives neuroendocrine prostate cancer progression by epigenetically upregulating FOXA2. J Pathol. 2021 Jan;253(1):106-118. doi: 10.1002/path.5557. Epub 2020 Nov 5. PMID: 33009820; PMCID: PMC7756255.