Anyaeche, V. I. | bioRxiv Science

bioRxiv2024

Identification of the MRTFA/SRF pathway as a critical regulator of quiescence in cancer.

Chemoresistance is a major driver of cancer deaths. One understudied mechanism of chemoresistance is quiescence. We used single cell culture to identify, retrieve, and RNA-Seq profile primary quiescent ovarian cancer cells (qOvCa). We found that many qOvCa differentially expressed genes are transcriptional targets of the Myocardin Related Transcription Factor/Serum Response Factor (MRTF/SRF) pathway. We also found that genetic disruption of MRTF-SRF interaction, or an MRTF/SRF inhibitor (CCG257081) impact qOvCa gene expression and induce a quiescent state in cancer cells. Suggesting a broad role for this pathway in quiescence, CCG257081 treatment induced quiescence in breast, lung, colon, pancreatic and ovarian cancer cells. Furthermore, CCG081 (i) maintained a quiescent state in patient derived breast cancer organoids and, (ii) induced tumor growth arrest in ovarian cancer xenografts. Together, these data suggest that MRTF/SRF pathway is a critical regulator of quiescence in cancer and a possible therapeutic target. SignificanceQuiescence is a critical driver of chemoresistance. The MRFT-SRF pathway regulates cancer cell quiescence and inhibiting the MRTF-SRF pathway can prevent the outgrowth of quiescent cancer cells and improve cancer outcomes.

cancer biology↗

bioRxiv2022

A twin UGUA motif directs the balance between gene isoforms through CFIm and the mTORC1 signaling pathway.

Alternative polyadenylation (APA) generates mRNA isoforms and diversifies gene expression. Here we report the identification of a twin UGUA motif, UGUAYUGUA, and its function in APA. Applying cTag-PAPERCLIP to Tsc1 conditional knockout mice, we discovered that the mTORC1 pathway balances expression of Trim9 isoforms. We showed that CFIm components, CPSF6 and NUDT21, promote Trim9/TRIM9-S expression in mouse and human, and we identified an evolutionarily conserved UGUAYUGUA motif that is critical for this regulation. We found additional CPSF6-regulated polyadenylation sites (PASs) with similar twin UGUA motifs in human, and we experimentally validated the twin UGUA motif functionality in BMPR1B, MOB4, and BRD4-L. Importantly, we showed that inserting a twin UGUA motif into a heterologous PAS was sufficient to confer regulation by CPSF6 and mTORC1. Our study reveals an evolutionarily conserved mechanism to regulate gene isoform expression and implicates possible gene isoform imbalance in cancer and neurologic disorders with mTORC1 pathway dysregulation.

molecular biology↗