Lim Su Jun, Li Jinghong, Li Willis X
Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, 14642, USA.
Department of Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
Mol Genet Genomics. 2025 Sep 2;300(1):84. doi: 10.1007/s00438-025-02293-z.
Oncogenic Ras mutations are prevalent in human cancers, yet the mechanisms by which Ras promotes tumorigenesis remain incompletely understood. In Drosophila, oncogenic Ras (Ras) 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 Ras-induced lethality and Ras-induced overgrowth and cell proliferation. Knockdown of CRIF exacerbated Ras 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.
致癌性Ras突变在人类癌症中普遍存在，然而Ras促进肿瘤发生的机制仍未完全明确。在果蝇中，致癌性Ras（Ras）会诱导组织过度生长和转移，但它必须克服的细胞限制尚不清楚。我们已确定果蝇CRIF（哺乳动物CR6相互作用因子1（CRIF1）的同源物）是Ras诱导的致死性、Ras诱导的过度生长和细胞增殖的修饰因子。敲低CRIF会加剧Ras表型，而CRIF过表达则会改善这些表型。此外，我们发现CRIF对于异染色质形成也是必需的，因为CRIF缺失会抑制位置效应斑驳（PEV）并降低异染色质蛋白1（HP1）和组蛋白H3赖氨酸9三甲基化（H3K9me3）的水平。CRIF与HP1发生物理相互作用，表明其在将HP1招募至异染色质中发挥作用。值得注意的是，CRIF并不调节HP1的转录或总蛋白水平，而是影响HP1的定位。我们的研究结果表明，CRIF通过负向调节细胞增殖和维持异染色质稳定性发挥肿瘤抑制作用。CRIF与HP1的相互作用及其在异染色质调节中的作用提示了一种将异染色质与Ras驱动的癌症中的肿瘤抑制联系起来的新机制。这些结果突出了CRIF作为潜在治疗靶点的地位，并为染色质调节与致癌信号之间的相互作用提供了新的见解。
