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. 2025 Sep 2;300(1):84.
doi: 10.1007/s00438-025-02293-z.

CRIF counteracts oncogenic Ras and regulates heterochromatin

Su Jun Lim  1 , Jinghong Li  2 , Willis X Li  3   4
Affiliations

CRIF counteracts oncogenic Ras and regulates heterochromatin

Su Jun Lim et al. Mol Genet Genomics. .

Abstract

Oncogenic Ras mutations are prevalent in human cancers, yet the mechanisms by which Ras promotes tumorigenesis remain incompletely understood. In Drosophila, oncogenic Ras (RasV12) induces tissue overgrowth and metastasis, but the cellular restraints it must overcome are unclear. We have identified Drosophila CRIF, the homolog of mammalian CR6-interacting factor 1 (CRIF1), as a modifier of RasV12-induced lethality and RasV12-induced overgrowth and cell proliferation. Knockdown of CRIF exacerbated RasV12 phenotypes, while CRIF overexpression ameliorated them. Further, we found that CRIF was also required for heterochromatin formation, as loss of CRIF suppressed position-effect variegation (PEV) and reduced the levels of Heterochromatin Proteins 1 (HP1) and Histone H3 Lysine 9 trimethylation (H3K9me3). CRIF physically interacted with HP1, suggesting a role in recruiting HP1 to heterochromatin. Notably, CRIF did not regulate HP1 transcription or total protein levels but influenced HP1 localization. Our findings demonstrate that CRIF functions as a tumor suppressor by negatively regulating cell proliferation and maintaining heterochromatin stability. CRIF's interaction with HP1 and its role in heterochromatin regulation suggest a novel mechanism linking heterochromatin to tumor suppression in Ras-driven cancers. These results highlight CRIF as a potential therapeutic target and provide new insights into the interplay between chromatin regulation and oncogenic signaling.

Keywords: Drosophila; CRIF; Heterochromatin; Oncogenic Ras; Tumor suppression.

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Conflict of interest statement

Declarations. Conflict of interest: The authors declare no competing financial or non-financial interests related to this work.

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