M1C mediates LINE-1 transcription in PARP inhibitor-treated prostate cancer cells.

Advanced castration-resistant prostate cancer (CRPC) is responsive to PARP inhibitors, but only in settings of defects in homologous recombination (HR). The oncogenic M1C protein drives CRPC progression; however, it is not known if M1C plays a role in the response to PARP inhibition. The present work demonstrates that M1C is induced by olaparib treatment of HR-competent CRPC cells. As a result, M1C drives (i) ATM expression, (ii) phosphorylation of KAP1(S824) and (iii) activation of STING, which have been linked to derepression of the LINE-1 (L1) retrotransposon. In this way, M1C is necessary for induction of (i) L1-5'UTR, L1-ORF1 and L1-ORF2 transcripts and (ii) the encoded ORF1p RNA binding protein. Activation of retrotransposons induces genomic instability and drug resistance. By extension, we show that M1C also activates HERV-K102/108 gag, pol and env genes and expression of the HERV-K ENV protein. Our work further demonstrates that M1C integrates L1 and HERV-K activation with induction of APOBEC3 (A3) genes that evolved to restrain genomic instability induced by these retrotransposons. Of translational relevance, these findings demonstrate that M1C (i) is essential for inducing L1, HERV-K and A3 expression and resistance of CRPC cells to olaparib, and (ii) is a target for advancing the treatment of HR-competent CRPC with PARP inhibitors.