RNA Splicing of the BHC80 Gene Contributes to Neuroendocrine Prostate Cancer Progression

Abstract

Background: Prostate adenocarcinoma (AdPC) progression to treatment-induced neuroendocrine prostate cancer (t-NEPC) is associated with poor patient survival. While AdPC and t-NEPC share similar genomes, they possess distinct transcriptomes, suggesting that RNA splicing and epigenetic mechanisms may regulate t-NEPC development. Objective: To characterize the role of alternative RNA splicing of the histone demethylase BHC80 during t-NEPC progression. Design, setting, and participants: The expression of BHC80 splice variants (BHC80-1 and BHC80-2) were compared between AdPC and t-NEPC patient tumors. Regulatory mechanisms of RNA splicing of the BHC80 gene were studied, and the signal pathways mediated by BHC80 splice variants were investigated in t-NEPC cell and xenograft models. Results: Global transcriptome analyses identified that the BHC80-2 variant is highly expressed in t-NEPC. Compared with the known histone demethylation activities of the BHC80 gene, we discovered a novel nonepigenetic action of BHC80-2, whereby BHC80-2 is localized in the cytoplasm to trigger the MyD88-p38-TTP pathway, which results in increased RNA stability of multiple tumor-promoting cytokines. While BHC80-2 does not induce neuroendocrine differentiation of cancer cells, it stimulates cell proliferation and tumor progression independent of androgen receptor signaling. Blockade of BHC80-2-regulated MyD88 signaling suppresses growth of several t-NEPC cell spheroid and xenograft models. Conclusions: Gain of function of BHC80-2 through alternative RNA splicing activates immune responses of cancer cells to promote t-NEPC development. Patient summary: The main obstacle to develop effective therapies for patients with t-NEPC is the lack of understanding on how t-NEPC is developed. Our study not only identifies a previously unknown BHC80-2-MyD88 signaling pathway that plays an important role during t-NEPC development, but also provides a proof of principle that targeting this signal pathway may offer an avenue to treat t-NEPC.

LIN28B promotes the development of neuroendocrine prostate cancer

“…LnNE and DuNE cells were reported from our previous studies (31,32). All cell culture conditions have been previously reported (12,14). All lines used in this study tested negative for mycoplasma contamination and were authenticated by short tandem repeat assays.…”

“…The development of t-NEPC is regulated by PCa cell lineage plasticity, whereby prostate adenocarcinoma (AdPC) cells acquire a pluripotent stem-like phenotype followed by redifferentiation to NE lineage or undergo a transdifferentiation process to emerge as an NE lineage for t-NEPC tumorigenesis (5). These processes involve complex context-dependent mechanisms, including genomic alterations (7)(8)(9)(10), epigenetic reprogramming (11)(12)(13), alternative RNA splicing (12,14), and aberrant activation of transcriptional factors (7,(13)(14)(15). The diversity of genomic backgrounds and variability of molecular pathways help explain the heterogeneity of t-NEPC (16) and multiple driver genes discovered to date (7)(8)(9)(10)(11)(12)(13)(14)(15).…”

“…LIN28B and SOX2 expression are co-upregulated in a subgroup of t-NEPC. To confirm LIN28B and SOX2 protein expression in t-NEPC using tumor samples from an independent patient cohort, we applied IHC on tissue microarrays (TMAs) from the Vancouver Prostate Centre (VPC) tissue bank containing 16 primary AdPC, 54 CRPC-AdPC, and 30 CRPC-NEPC tissue cores that were previously characterized by histology, NE, and AdPC marker status (12,36,37). The specificity of the LIN28B antibody for IHC was confirmed by using tissue slides with known LIN28B mRNA and protein status ( Figure 1I).…”

PNO1 promotes cell proliferation in prostate cancer

“…In this study, we identified 291 up-regulated and 498 down-regulated targets of PNO1 in PCa. Bioinformatics analysis showed PNO1 was involved in regulating multiple cancer related pathways, such as DNA repair [25], regulation of angiogenesis [26,27], translational initiation [28,29], RNA splicing [30,31], and cellular response to hypoxia [32,33]. Emerging studies showed these pathways played crucial roles in PCa progression and treatment.…”

The epigenetic and transcriptional landscape of neuroendocrine prostate cancer

“…SRRM4 is a splicing factor specifically required for neural cell differentiation that was found to be elevated in NEPC (Zhang et al 2015) and, by careful analysis of whole-transcriptome sequencing data, implicated in the majority (>66%) of splicing alterations seen in this disease state (Li et al 2017). Key targets of SRRM4 include REST, a negative regulator of neurogenesis (Li et al 2017), as well Bif-1 (Gan et al 2018), MEAF6 (Lee et al 2017), and the histone demethylase BHC80 (Li et al 2019). The identities and roles of other splicing factors beyond SRRM4 that contribute to neuroendocrine lineage plasticity remain to be determined.…”