ESPEYB21 14. The Year in Science and Medicine Epi-/Genetics (3 abstracts)
14.8. Histone H2A Lys130 acetylation epigenetically regulates androgen production in prostate cancer
Nguyen T , Sridaran D , Chouhan S , Weimholt C , Wilson A , Luo J , Li T , Koomen J , Fang B , Putluri N , Sreekumar A , Feng FY , Mahajan K & Mahajan NP.
Nat Commun. 2023 Jun 9;14(1):3357. doi: 10.1038/s41467-023-38887-7
Brief Summary:This study reveals how castration resistant prostate cancers (CRPC) can produce androgens and become resistant to the inhibitor of androgen production abiraterone. The authors uncover dual phosphorylated-SREBF1 as a sensor of androgen deficiency. Its nuclear translocation and deposition of H2A-K130ac epigenetic marks activates a distinct transcription program that includes SREBF1. This will then lead to intratumoral cholesterol and androgen biosynthesis, liberating CRPCs from their dependence of testicular androgen production and escaping the inhibition due to abiraterone treatment. Thus, SREBF1 Tyr673/951-phosphorylation or the H2A-K130ac epigenetic mark could become new treatment targets.
Prostate cancers (PCa) depend initially on testicular testosterone to flourish. But castration or treatment with the CYP17 inhibitor arbiraterone becomes inefficient within a short time resulting in castration resistant prostate cancers (CRPC). Previously, it was observed that prostate cancers exhibit a distinct shift towards de novo lipid biosynthesis and steroidogenesis. Here, it is now shown that this shift is mediated by the protein SREBF1 and the enzyme GCN5, which modify histones to activate genes responsible for cholesterol and lipid production, and that this leads to enhanced androgen production within the cancer tissue. Researchers also demonstrate in mice that inhibiting these pathways with specific drugs, including afatinib (an EGFR inhibitor) and a GCN5 inhibitor, significantly reduces tumor growth, suggesting new treatment approaches.
This study demonstrates that androgen production in tumors can be enhanced through very complex regulation of lipid biosynthesis and epigenetic modulation that differs fundamentally from normal physiology. Understanding such alternative (tumor-specific) pathways provides new perspectives on biology and may provide clinical opportunities for diagnostic and therapeutic interventions in other androgen-related disorders, e.g., PCOS.
Volume 21
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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