SLX4IP-mediated telomere maintenance is essential for androgen receptor-independent castration-resistant prostate cancer

Abstract

ABSTRACTIn advanced prostate cancer, resistance to androgen deprivation therapy is achieved through numerous mechanisms, including loss of the androgen receptor (AR) allowing for AR-independent growth. Therapeutic options are limited for AR-independent castration-resistant prostate cancer, and defining mechanisms critical for its survival is of utmost importance for targeting this lethal disease. Our studies have focused on defining the telomere maintenance mechanism (TMM) required for castration-resistant prostate cancer (CRPC) cell survival. TMMs are responsible for telomere elongation to instill replicative immortality and prevent senescence, with the two TMM pathways available being telomerase and alternative lengthening of telomeres (ALT). Here, we show that AR-independent CRPC exhibits ALT hallmarks and limited telomerase expression and activity, whereas AR-dependent models use telomerase for telomere maintenance. AR-independent CRPC exhibited elevated levels of SLX4IP, a protein implicated in TMM switching. SLX4IP overexpression in AR-dependent CRPC C4-2B cells promoted ALT hallmarks in vitro. SLX4IP knockdown in AR-independent CRPC cells (DU145 and PC-3) led to the loss of ALT hallmarks, dramatic telomere shortening, induction of senescence, and reduced tumor volume. Using an in vitro model of CRPC progression, induction of neuroendocrine differentiation in AR-dependent CRPC cells promoted ALT hallmarks in an SLX4IP-dependent manner. Lack of sufficient SLX4IP expression prevented ALT hallmarks rendering a TMM deficient environment, thus inducing senescence. This study demonstrates a unique reliance of AR-independent CRPC on SLX4IP-mediated ALT. Furthermore, ALT hallmark inhibition via SLX4IP induces senescence, thereby abolishing the replicative immortality of AR-independent CRPC.