Oncogenic MAGEA4 directs neuroendocrine differentiation and survival in prostate cancer cells through the SIRT1/Acetyl-p53/BCL-2 axis.
Neuroendocrine prostate cancer (NEPC) is a highly aggressive and therapy-resistant subtype of prostate cancer (PCa) that emerges following the androgen receptor (AR) targeted therapies. Identification of potential molecular drivers governing neuroendocrine differentiation (NED) and survival is critical for developing therapeutic strategies. Cancer-testis antigens of the Melanoma-associated antigen family (MAGE) are the emerging players of oncogenic regulators. However, their role in NEPC remains unexplored.
Proteomic and transcriptomic analyses were performed to identify differential expression of target proteins in NEPC. Functional characterization of MAGEA4 was performed using stable overexpression, siRNA-mediated knockdown in androgen-dependent/independent, and NEPC cell lines. For target validation, neuroendocrine markers, morphological characteristics, apoptotic signaling, oxidative pathways, and cell survival were evaluated using molecular, biochemical, and pharmacological approaches targeting SIRT1, p53 acetylation, BCL-2/BCL-XL and NRF2.
MAGEA4 was upregulated in NEPC cells and in advanced prostate cancer tissues. Overexpression of MAGEA4 induced neuroendocrine differentiation, promoted androgen-independent survival, and conferred resistance to apoptosis. Furthermore, MAGEA4 upregulated SIRT1 activity, which deacetylated p53, thereby suppressing pro-apoptotic signaling. Additionally, MAGEA4 enhanced the oxidative stress resistance through activation of the SIRT1/PGC-1α/NRF2 axis, suggesting a role in retaining the NED phenotype. In MAGEA4-positive cells, inhibition of BCL-2 and/or NRF2 attenuated the neuroendocrine characteristics, suggesting therapeutic vulnerability.
These findings highlight that MAGEA4 may contribute to neuroendocrine differentiation and survival in prostate cancer cells, and may represent a potential therapeutic vulnerability in aggressive prostate cancers.
Proteomic and transcriptomic analyses were performed to identify differential expression of target proteins in NEPC. Functional characterization of MAGEA4 was performed using stable overexpression, siRNA-mediated knockdown in androgen-dependent/independent, and NEPC cell lines. For target validation, neuroendocrine markers, morphological characteristics, apoptotic signaling, oxidative pathways, and cell survival were evaluated using molecular, biochemical, and pharmacological approaches targeting SIRT1, p53 acetylation, BCL-2/BCL-XL and NRF2.
MAGEA4 was upregulated in NEPC cells and in advanced prostate cancer tissues. Overexpression of MAGEA4 induced neuroendocrine differentiation, promoted androgen-independent survival, and conferred resistance to apoptosis. Furthermore, MAGEA4 upregulated SIRT1 activity, which deacetylated p53, thereby suppressing pro-apoptotic signaling. Additionally, MAGEA4 enhanced the oxidative stress resistance through activation of the SIRT1/PGC-1α/NRF2 axis, suggesting a role in retaining the NED phenotype. In MAGEA4-positive cells, inhibition of BCL-2 and/or NRF2 attenuated the neuroendocrine characteristics, suggesting therapeutic vulnerability.
These findings highlight that MAGEA4 may contribute to neuroendocrine differentiation and survival in prostate cancer cells, and may represent a potential therapeutic vulnerability in aggressive prostate cancers.