Firefox, a protein encoded by circular PVT1, is essential for MYC-driven oncogenesis.

Authors

Ashutosh Tiwari, Utkarsha Paithane, Kojiro Tashiro, Bryan Hall, Jordan Friedlein, Mayank Saraswat, Olivier Saulnier, Karina Barbosa, Quang Trinh, Shrawantee Saha, Aditi Soni, Takuma Nakashima, Rabi Murad, Svetlana Maurya, Owen S Chapman, Brian James, Anders Erickson, Jashua T Lange, Robyn Leary, Jyotika Varshney, Badrinath Konety, Scott M Dehm, Yasuhiko Kawakami, David A Largaespada, William A Weiss, Lincoln Stein, Lukas Chavez, Hiromichi Suzuki, Sihan Wu, Jianhua Zhao, Aniruddha J Deshpande, Michael D Taylor, Robert J Wechsler-Reya, Anindya Bagchi

Published in

Genes & development. Aug 19, 2026. Epub Aug 19, 2026.

Abstract

MYC-driven (MYC⁺) cancers are highly aggressive and often fatal. MYC dysregulation is a key event in these cancers, yet MYC overexpression alone is often insufficient to initiate or sustain tumorigenesis. Plasmocytoma variant translocation 1 (PVT1), a long noncoding RNA (lncRNA) adjacent to MYC on chromosome 8q24, is frequently co-amplified with MYC in many of these cancers. Our prior work showed that PVT1 potentiates MYC function, although the underlying mechanism has remained unclear. Here we show that, in addition to amplification with MYC, genomic rearrangements at PVT1 frequently involve unbalanced translocations that asymmetrically enrich 5'-PVT1 while depleting 3'-PVT1 The retained 5'-PVT1 region generates a circular RNA, CircPVT1, that encodes a novel protein we have named Firefox (FFX). We show that FFX is essential for MYC-mediated oncogenic signaling, as its depletion markedly reduces MYC protein abundance and transcriptional output. Mechanistically, FFX stimulates AKT-mTORC1 signaling and enhances cap-dependent translational and biosynthetic capacity, thereby establishing a self-reinforcing oncogenic circuit that amplifies MYC activity. Inducible depletion of FFX in vivo significantly impairs tumor growth in MYC⁺ xenograft models. These findings define FFX as a critical effector within the MYC-PVT1 locus and reveal a therapeutically actionable vulnerability in MYC⁺ cancers.

PMID:
42618323
Bibliographic data and abstract were imported from PubMed on 20 Aug 2026.

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