Abstract 3062: ROMO1 mediates mitochondrial function links to neuroendocrine differentiation of prostate cancer enhancement by the nuclear PKLR/MYCN/MAX complex

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Abstract Conventional treatment of prostate cancer (PCa) uses androgen deprivation therapy (ADT) to inhibit androgen receptor (AR) signaling-driven tumor progression. ADT-induced PCa recurrence may progress to AR-negative phenotype with neuroendocrine (NE) features on histology, which is associated with metabolic disturbances and poor prognosis. However, the association between the metabolic pathways that regulate mitochondrial function and promote NE differentiation (NED) in PCa remains unclear. Here, we show a regulatory mechanism in PCa pathogenesis whereby overexpression of pyruvate kinase L/R (PKLR) mediates mitochondrial disorder and oxidative stress through upregulation of reactive oxygen species modulator 1 (ROMO1), thereby promoting NED-related aggressiveness. ADT mediates the nuclear translocation of PKLR, which binds to the MYCN/MAX complex to upregulate ROMO1 and NE-related genes, leading to mitochondrial dysfunction and NED in PCa. Targeting nuclear PKLR/MYCN using bromodomain and extra-terminal motif (BET) inhibitors has the potential to reduce PKLR/MYCN-driven NED. Abundant ROMO1 in serum samples may provide prognostic information in patients with ADT-induced NED. Our findings link ADT resistance-driven metabolic reprogramming to NED of PCa through upregulation of PKLR/MYCN/ROMO1 signaling, and further explored the clinical significance of targeting the nuclear PKLR/MYCN complex and evaluated serum ROMO1 as a potential biomarker for aggressive NE-like PCa. Citation Format: Yen-Nien Liu, Wei-Yu Chen, Phan Vu Thuy Dung, Hsiu-Lien Yeh, Zi-Qing Chen, Wan-Hsin Wang, Yu-Ching Wen. ROMO1 mediates mitochondrial function links to neuroendocrine differentiation of prostate cancer enhancement by the nuclear PKLR/MYCN/MAX complex [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 3062.

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