Transient Sox9 Expression Facilitates Resistance to Androgen-Targeted Therapy in Prostate Cancer

Abstract

Purpose: Patients with metastatic prostate cancer are increasingly presenting with treatment-resistant, androgen receptor-negative/ low (AR À/Low ) tumors, with or without neuroendocrine characteristics, in processes attributed to tumor cell plasticity. This plasticity has been modeled by Rb1/p53 knockdown/knockout and is accompanied by overexpression of the pluripotency factor, Sox2. Here, we explore the role of the developmental transcription factor Sox9 in the process of prostate cancer therapy response and tumor progression.Experimental Design: Unique prostate cancer cell models that capture AR À/Low stem cell-like intermediates were analyzed for features of plasticity and the functional role of Sox9. Human prostate cancer xenografts and tissue microarrays were evaluated for temporal alterations in Sox9 expression. The role of NF-kB pathway activity in Sox9 overexpression was explored.Results: Prostate cancer stem cell-like intermediates have reduced Rb1 and p53 protein expression and overexpress Sox2 as well as Sox9.Sox9 was required for spheroid growth, and overexpression increased invasiveness and neural features of prostate cancer cells. Sox9 was transiently upregulated in castration-induced progression of prostate cancer xenografts and was specifically overexpressed in neoadjuvant hormone therapy (NHT)-treated patient tumors. High Sox9 expression in NHT-treated patients predicts biochemical recurrence. Finally, we link Sox9 induction to NF-kB dimer activation in prostate cancer cells.Conclusions: Developmentally reprogrammed prostate cancer cell models recapitulate features of clinically advanced prostate tumors, including downregulated Rb1/p53 and overexpression of Sox2 with Sox9. Sox9 is a marker of a transitional state that identifies prostate cancer cells under the stress of therapeutic assault and facilitates progression to therapy resistance. Its expression may index the relative activity of the NF-kB pathway.

STAT3 inhibition with galiellalactone effectively targets the prostate cancer stem-like cell population

“…Nevertheless, our spheres express high levels of several pluripotency genes, including NANOG, ALDH1A1, SOX2, OCT4 and KLF4, among others. Several studies have validated the implication of these genes in the regulation of the PCa stem cell niche, which confirms that these spheres retain stemness characteristics [33][34][35][36][37] . Indeed, our data indicate that a pattern of different embryonic pluripotency genes is crucial for the identification of docetaxel-resistant prostate CSCs.…”

Transcriptional Inactivation of TP53 and the BMP Pathway Mediates Therapy-induced Dedifferentiation and Metastasis in Prostate Cancer

“…GSEA indicated that KRAS_SIGNALING_UP and inflammatory signatures dependent on NF-κB or JAK-STAT3 signaling were amongst the top 10 Hallmark signatures induced by LDN193189 or enzalutamide (Figure 6P and S6N). The top genes within these signatures upregulated by LDN193189 included proteins potentially involved in prostate cancer therapy resistance and metastasis, such as the Notch ligand JAG1 (Domingo-Domenech et al, 2012), the lineage transcription factor SOX9 (Nouri et al, 2020), the inhibitor of apoptosis protein BIRC3 (Silke and Vucic, 2014), and the cytokine CCL2 (Su et al, 2019). In addition, CCL20 has been implicated in chemotherapy resistance in breast cancer (Chen et al, 2018).…”

Mechanisms of enzalutamide resistance in castration‐resistant prostate cancer and therapeutic strategies to overcome it

“…SOX9 is a recently discovered SOX family member that is up‐regulated in stem‐like reprogrammed prostate cancer cells. Transient SOX9 expression facilitates the resistance to enzalutamide via NF‐κB dimer activation (Nouri et al, 2020). Additionally, RE1‐silencing transcription factor ( REST ), another epigenetic remodelling regulator, mainly binds to chromatin in the proximity of neuron‐specific genes.…”