Honeybadger, a micropeptide encoded by an alternative PVT1 transcript, is a critical negative regulator of RAS–MAPK signaling in MYC-driven tumors
Year: 2026
Type: preprint
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 Ser 62 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.
Source: Genes & Development
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
Institutions: Sanford Burnham Prebys Medical Discovery Institute, National Cancer Institute, Jikei University School of Medicine, Inserm, Université Paris Sciences et Lettres, Hospital for Sick Children, Institut Curie, Ontario Institute for Cancer Research, National Cancer Center Research Institute, Center for Neuro-Oncology, Dana-Farber Cancer Institute, University of Toronto, Columbia University Irving Medical Center, Herbert Irving Comprehensive Cancer Center, Rush University Medical Center, University of Minnesota, Allina Health, Masonic Cancer Center, University of California, San Francisco, UCSF Helen Diller Family Comprehensive Cancer Center, Cold Spring Harbor Laboratory, Baylor College of Medicine, Texas Children's Hospital, Dan L Duncan Comprehensive Cancer Center
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: diamond
Funders: U.S. Department of Defense, American Association for Cancer Research, American Cancer Society, Cancer Prevention and Research Institute of Texas, Tobacco-Related Disease Research Program, Genome Canada, Government of Ontario, Government of Canada, Genome British Columbia, Cancer Research UK, National Institute for Health and Care Research, Brain Tumour Charity, Terry Fox Research Institute, National Institutes of Health, Stand Up To Cancer, Canadian Institutes of Health Research, Canadian Cancer Society Research Institute, National Cancer Institute, DOD Prostate Cancer Research Program
Awards: G1601614885, G1935523325, G1985116395, G2061320564, G2072947043, G2166824534, G2175480743, G2292160513, G2569015222, G264098294, G2682813508, G2725826772, G2817447826, G285073136, G2944979169, G3182939611, G3294626078, Recruitment of Established Investigators, G3655805575, G3725487078, G3768254803, G3966651400, G4031651457, G5115508367, G521478274, G5346823456, G5357747714, G5545467108, G5812395302, G6069625257, G6421542061, Functional Analysis of Low Copy Number Gain of Human 8q24 in Breast Cancer, G668039142, G7116957482, G7133393657, G7712489262, G7756677588, G7848911912, G7890600570, G7918806922, G8156467647, G8190402583, SPORE in Brain Cancer, G949115552
OpenAlex ID: W7203789126
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