Honeybadger, a micropeptide encoded by an alternative PVT1 transcript, is a critical negative regulator of RAS-MAPK signaling in MYC-driven tumors.

Authors

Utkarsha Paithane, Ashutosh Tiwari, Bryan Hall, Kojiro Tashiro, Olivier Saulnier, Quang Trinh, Aditi Soni, Takuma Nakashima, Andrey A Bobkov, Lynn Miya Fujimoto, Mayank Saraswat, Shahab Sarmashghi, Liam D Hendrikse, Meher Beigi Masihi, Shrawantee Saha, Srija Ghosh, Brian James, Anders Erickson, Tanja Eisemann, Theophilos Tzaridis, Badrinath Konety, Scott M Dehm, Rameen Beroukhim, Lukas Chavez, David A Largaespada, Lincoln Stein, Hiromichi Suzuki, William A Weiss, Johannes Yeh, Jianhua Zhao, Robert J Wechsler-Reya, Michael D Taylor, Anindya Bagchi

Published in

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

Abstract

Genomic rearrangements can drive cancer through mechanisms that extend beyond classical oncogenic fusions such as BCR-ABL A substantial fraction of these events involve long noncoding RNAs (lncRNAs), yet their functional impact on tumorigenesis has remained largely opaque. The lncRNA plasmacytoma variant translocation 1 (PVT1), positioned adjacent to MYC at chromosome 8q24, is among the most frequently altered loci in MYC-driven (MYC⁺) cancers. We recently showed that PVT1 translocations produce a characteristic asymmetric architecture that preserves the 5'-PVT1 region, generating a circular RNA (CircPVT1) that encodes Firefox (FFX), a novel oncoprotein that activates AKT-mTORC1 signaling and cooperates with MYC. Here, we uncover a complementary and opposing function for the deleted 3'-PVT1 segment, which encodes a tumor-suppressive micropeptide we term Honeybadger (HNB). HNB binds KRAS and dampens RAS-MAPK signaling, and its loss derepresses this pathway and stabilizes MYC via Ser⁶² phosphorylation. Thus, a single class of structural alterations at PVT1 simultaneously installs FFX-mediated AKT-mTORC1 activation and removes HNB-mediated RAS-MAPK regulation, creating a dual mechanism that synergistically amplifies MYC output. This oncoprotein gain coupled with tumor-suppressor loss provides a mechanistic explanation for the particularly poor prognosis of PVT1-rearranged cancers and establishes PVT1 as a central regulatory hub in MYC⁺ malignancies.

PMID:
42618324
Bibliographic data and abstract were imported from PubMed on 20 Aug 2026.

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