Dependence on MUC1-C in Progression of Neuroendocrine Prostate Cancer

Abstract

Castration resistant prostate cancer (CRPC) is responsive to androgen receptor (AR) axis targeted agents; however, patients invariably relapse with resistant disease that often progresses to neuroendocrine prostate cancer (NEPC). Treatment-related NEPC (t-NEPC) is highly aggressive with limited therapeutic options and poor survival outcomes. The molecular basis for NEPC progression remains incompletely understood. The MUC1 gene evolved in mammals to protect barrier tissues from loss of homeostasis. MUC1 encodes the transmembrane MUC1-C subunit, which is activated by inflammation and contributes to wound repair. However, chronic activation of MUC1-C contributes to lineage plasticity and carcinogenesis. Studies in human NEPC cell models have demonstrated that MUC1-C suppresses the AR axis and induces the Yamanaka OSKM pluripotency factors. MUC1-C interacts directly with MYC and activates the expression of the BRN2 neural transcription factor (TF) and other effectors, such as ASCL1, of the NE phenotype. MUC1-C also induces the NOTCH1 stemness TF in promoting the NEPC cancer stem cell (CSC) state. These MUC1-C-driven pathways are coupled with activation of the SWI/SNF embryonic stem BAF (esBAF) and polybromo-BAF (PBAF) chromatin remodeling complexes and global changes in chromatin architecture. The effects of MUC1-C on chromatin accessibility integrate the CSC state with the control of redox balance and induction of self-renewal capacity. Importantly, targeting MUC1-C inhibits NEPC self-renewal, tumorigenicity and therapeutic resistance. This dependence on MUC1-C extends to other NE carcinomas, such as SCLC and MCC, and identify MUC1-C as a target for the treatment of these aggressive malignancies with the anti-MUC1 agents now under clinical and preclinical development.

Keywords: CSC; MUC1-C; NEPC; chromatin remodeling; lineage plasticity.

Figure 2

MUC1-C drives NEPC dedifferentiation. MUC1-C binds directly to the MYC HLH/LZ domain and contributes to the induction of MYC target genes. MUC1-C/MYC complexes occupy the BRN2 promoter and induce BRN2 expression. BRN2 induces SOX2 expression [51]. In addition, MUC1-C drives KLF4 and OCT4, which are collectively referred to as OSKM factors, and are sufficient for inducing pluripotency and dedifferentiation of somatic cells [57]. In addition, MUC1-C activates the inflammatory NF-κB p65 pathway and, by binding directly to NF-κB p65, promotes the activation of NF-κB p65 target genes [61], including (i) ZEB1 and thereby EMT and stemness, and (ii) EZH2 and epigenetic reprogramming [45,62]. In this way, MUC1-C integrates activation of the MYC and NF-κB p65 pathways to drive NEPC dedifferentiation and self-renewal. Figure modified from [24].

Figure 1

The activation of MUC1-C by loss of homeostasis contributes to wound healing and progression to cancer. The transmembrane MUC1-C subunit is expressed at the apical borders of polarized epithelial cells where it is poised to respond to stress. The activation of MUC1-C in response to loss of homeostasis induces the Yamanaka pluripotency factors, EMT and epigenetic reprogramming. MUC1-C also contributes to inflammatory, proliferative and remodeling responses associated with wound repair. These responses are, in principle, reversible with healing; however, prolonged activation of MUC1-C in settings of chronic inflammation with the remodeling of chromatin drive progression to cancer. Figure modified from [43].

Figure 3

MUC1-C activates the esBAF chromatin remodeling complex in driving the NEPC CSC state. In parallel with the induction of the BRN2 and NE phenotype, MUC1-C interacts with E2F1 and induces the expression of the esBAF subunits. MUC1-C forms a nuclear complex with BRG1 and ARID1A, which activates the NOTCH1 gene, NOTCH1 expression and NOTCH1 target genes. MUC1-C-induced activation of esBAF also promotes NANOG expression and self-renewal capacity. These findings demonstrate that MUC1-C integrates the MYC and E2F1 pathways in driving NEPC dedifferentiation. Figure modified from [73].

Figure 4

MUC1-C→E2F1 signaling integrates the activation of the esBAF and PBAF chromatin remodeling complexes. MUC1-C forms nuclear complexes with E2F1 that activate the expression of the esBAF and PBAF subunits. MUC1-C associates with PBRM1 and NRF2 in increasing the chromatin accessibility of NRF2 target genes, including SLC7A11, G6PD and PGD, that regulate redox balance. MUC1-C-induced activation of PBRM1/PBAF also contributes to the expression of the OSKM + NANOG pluripotency factors and integration with the ARID1A/esBAF complex that drives EMT, NOTCH1 and the NEPC CSC state. Figure modified from [84].

Figure 5

MUC1-C integrates the induction of the esBAF and PBAF chromatin remodeling complexes with the chronic activation of the IFNG pathway and immunosuppression. MUC1-C activates the IFNGR1 gene by forming a complex with JUN and ARID1A that increases chromatin accessibility, H3K4 trimethylation and IFNGR1 expression. MUC1-C thereby contributes to upregulation of STAT1 and IRF1, and in turn interacts with IRF1 and PBRM1 to drive the expression of (i) IDO1, WARS and PTGES that metabolically suppress the TME, and (ii) ISG15 and SERPINB9, which inhibit T cell function. Consistent with the induction of these immunosuppressive effectors, MUC1 associates with immune cell-depleted cold TMEs. Figure modified from [92].