YAP1 overexpression contributes to the development of enzalutamide resistance by induction of cancer stemness and lipid metabolism in prostate cancer

Abstract

Metastatic castration-resistant prostate cancer (mCRPC) is a malignant and lethal disease caused by relapse after androgen-deprivation (ADT) therapy. Since enzalutamide is innovated and approved by US FDA as a new treatment option for mCRPC patients, drug resistance for enzalutamide is a critical issue during clinical usage. Although several underlying mechanisms causing enzalutamide resistance were previously identified, most of them revealed that drug resistant cells are still highly addicted to androgen and AR functions. Due to the numerous physical functions of AR in men, innovated AR-independent therapy might alleviate enzalutamide resistance and prevent production of adverse side effects. Here, we have identified that yes-associated protein 1 (YAP1) is overexpressed in enzalutamide-resistant (EnzaR) cells. Furthermore, enzalutamide-induced YAP1 expression is mediated through the function of chicken ovalbumin upstream promoter transcription factor 2 (COUP-TFII) at the transcriptional and the post-transcriptional levels. Functional analyses reveal that YAP1 positively regulates numerous genes related to cancer stemness and lipid metabolism and interacts with COUP-TFII to form a transcriptional complex. More importantly, YAP1 inhibitor attenuates the growth and cancer stemness of EnzaR cells in vitro and in vivo. Finally, YAP1, COUP-TFII, and miR-21 are detected in the extracellular vesicles (EVs) isolated from EnzaR cells and sera of patients. In addition, treatment with EnzaR-EVs induces the abilities of cancer stemness, lipid metabolism and enzalutamide resistance in its parental cells. Taken together, these results suggest that YAP1 might be a crucial factor involved in the development of enzalutamide resistance and can be an alternative therapeutic target in prostate cancer.

Extracellular Vesicles in Advanced Prostate Cancer: Tools to Predict and Thwart Therapeutic Resistance

“…These results suggest that TSP1 could be employed as a biomarker to predict resistance to ARPIs and to diagnose NED in CRPC patients [109]. Another study described the expression of YAP1 and COUP-TFII in EVs from LNCaP-Enzalutamide resistant cells as well as sera from patients resistant to enzalutamide [110].…”

“…A miR-array study has also identified 29 deregulated miRNAs, 19 upregulated and 10 downregulated, in EVs samples derived from two paclitaxel resistant PCa cells (PC3 and DU145) compared with their parental cells, but miR expression in patients has not been investigated [86]. miR-21 expression was increased in EVs from enzalutamide resistant LNCaP cells as well as in sera of enzalutamide resistant patients [110].…”

Emerging Proteins in CRPC: Functional Roles and Clinical Implications

“…Moreover, DECR1 deletion decreased lipid metabolism of CRPC in vivo (6). Another study discovered that knockdown of YAP1 led to restored lipid content and reduced free fatty acid level in enzalutamide-resistant cells (20).…”

Interaction between prostate cancer stem cells and bone microenvironment regulates prostate cancer bone metastasis and treatment resistance

“…The important transcription regulators, SOX2, OCT4, and NANOG, contribute to the maintenance of the pluripotent state of CSCs. Some studies indicated that inhibition of androgen receptor (AR) function increases the stemness of PCSCs [44,45]. MDM2 mediates AR degradation to maintain the pluripotency of PCSCs.…”