GRPR-induced FAM135A expression promote perineural invasion in prostate cancer

Abstract

<p>Perineural invasion (PNI) is an independent adverse prognostic marker for prostate cancer (PCa) metastasis. Gastrin releasing peptide receptor (<em>GRPR</em>) targeted imaging and therapeutics have entered clinical trials, while its role in PCa perineural invasion remains unclear. Here, we uncovered Family With Sequence Similarity 135 Member A ༈FAM135A༉a dominant PNI driver activated by GRPR in PCa. First, PNI-PCa tissue showed higher neuroactive ligand-receptor interaction activity, and with <em>FAM135A</em> being the most notable marker in PNI group. Then in-vitro experiments using a co-culture system of PCa cells (including AR-positive LNCaP and AR-negative DU145/PC3) showed that FAM135A silencing abrogated tumor malignancy and neural invasion. Moreover, in vivo PCa-Sciatic nerve invasion mouse model demonstrated <em>FAM135A</em> inhibition controls tumor growth and improves motor function. Interestingly, <em>FAM135A</em> is nucleus enriched and its nuclear translocation is mediated by protein cytoplasmic-nuclear transporter <em>RAN</em>. Mechanistically, RNA-Seq and ChIP-Seq analyses identified Teneurin Transmembrane Protein 3 (<em>TENM3</em>) as a transcriptional target of nFAM135A, and <em>TENM3</em> plays an essential role in nFAM135A-induced cancer-nerve invasion. Notably, <em>FAM135A</em> is ultimately activated by Gastrin Releasing Peptide GRP and its receptor GRPR. Moreover, pharmacological GRPR inhibitor represses <em>FAM135A</em> expression via <em>MED15</em> activation. Together, we unveil <em>FAM135A</em> as an oncodriver and biomarker of PCa perineural invasion, and provide a novel strategy for PCa innervation therapeutics.<br></p>