Cancer researchers have identified a previously hidden molecular partnership that may help explain why the protein c-Myc becomes so destructive in tumors. In a study published in Nature Chemical Biology, Milione, Tong, Wolfe and colleagues used a light-triggered proximity-labeling strategy to map proteins found near c-Myc inside living cancer cells. Their approach revealed SLK, a kinase best known for roles in cell signaling and cytoskeletal regulation, as a cancer-associated co-regulator of c-Myc. The discovery adds a new layer to the biology of one of cancer’s most powerful and difficult-to-target drivers, while also pointing toward a possible vulnerability that is more selective for malignant cells than for normal tissue.
c-Myc is a transcription factor, meaning that it controls gene activity rather than acting as a conventional enzyme with an obvious drug-binding pocket. It regulates networks involved in cell growth, metabolism, protein production and division. In healthy tissues, c-Myc activity is usually tightly controlled and rises only when cells receive appropriate signals. In many cancers, however, the MYC gene is amplified, overexpressed or functionally deregulated. The resulting excess of c-Myc can push cells into a state of relentless proliferation, but its broad importance in normal biology makes direct inhibition challenging. Scientists have therefore increasingly focused on the proteins that work alongside c-Myc, hoping to disrupt tumor-specific support systems rather than eliminate c-Myc itself.
The researchers turned to photoproximity labeling to search for those support systems. Conventional biochemical techniques often require proteins to be extracted from cells, separated and purified, conditions that can cause weak or transient interactions to disappear. Proximity labeling addresses this problem by marking proteins located within a very small molecular neighborhood of a protein of interest. In the photochemical version, exposure to light activates a labeling catalyst positioned near c-Myc. Short-lived reactive species then attach molecular tags to nearby proteins, creating a chemical record of the local environment. Tagged proteins can subsequently be collected and identified by mass spectrometry, allowing researchers to examine c-Myc’s surroundings even when the interactions are brief, indirect or dependent on the cellular context.
That distinction is important because c-Myc does not operate alone at a single stable molecular site. It moves through the nucleus, binds DNA in cooperation with other transcriptional regulators and recruits complexes that modify chromatin and assemble the machinery needed for gene expression. A protein detected near c-Myc is not automatically a direct binding partner, and proximity labeling cannot by itself prove a physical interaction. It can, however, reveal candidates that conventional affinity-purification approaches may miss. The study used this spatial information as a starting point, identifying SLK among the proteins associated with the c-Myc neighborhood and then investigating whether the relationship had functional consequences in cancer cells.
SLK, or STE20-like kinase, belongs to a family of enzymes that transfer phosphate groups to other proteins. Such phosphorylation events can change a protein’s activity, stability, localization or ability to interact with additional partners. SLK has previously been linked to processes including cell movement, cytoskeletal organization and signaling responses, but its connection to c-Myc places it in a different biological framework. The findings indicate that SLK can act as a co-regulator of c-Myc-dependent programs, helping malignant cells maintain gene-expression patterns associated with growth and survival. Rather than being merely a passive neighbor, SLK appears to contribute to the functional environment that allows c-Myc to exert its oncogenic effects.
The cancer-specific character of the relationship is one of the study’s most significant features. According to the researchers, the c-Myc–SLK regulatory connection is stronger or more consequential in cancer cells than in nonmalignant counterparts. This suggests that tumors may become dependent on a signaling arrangement that normal cells either do not use or can tolerate losing. Such differences are highly valuable in drug development. A treatment aimed at SLK, or at the molecular interface linking SLK to c-Myc, might weaken c-Myc-driven tumors while causing less damage to healthy cells than a strategy designed to suppress c-Myc throughout the body. The work does not yet establish a clinically ready therapy, but it identifies a potential point of intervention within a notoriously difficult cancer pathway.
The study also illustrates how spatial proteomics is changing the search for cancer mechanisms. Instead of asking only which proteins can be pulled down with a target under artificial conditions, scientists can ask which proteins occupy its immediate vicinity inside intact cells, and whether that neighborhood changes between normal and malignant states. Light provides an especially useful trigger because labeling can be initiated at a chosen moment and, in principle, restricted to a defined experimental window. This temporal control may help distinguish stable molecular partnerships from short-lived encounters created by signaling, stress or changes in transcriptional activity. Combined with genetic perturbation, imaging, biochemical validation and gene-expression analysis, photoproximity labeling can turn an initially broad list of nearby proteins into a map of functional dependencies.
The findings may also help explain why tumors with similar levels of c-Myc can behave differently. Cancer is not governed by a single oncogene in isolation; the impact of a transcription factor depends on the signaling networks, chromatin landscape and protein partners available in each cell. If SLK supports a particular c-Myc-driven state, tumors with elevated SLK activity could respond differently to therapies than tumors that rely on other co-regulators. Measuring both proteins, or the gene programs controlled by their partnership, might eventually contribute to patient stratification. At present, however, such clinical applications remain speculative. The interaction must be examined across additional tumor types, genetic backgrounds and patient-derived models before its predictive or therapeutic value can be assessed.
Several questions remain open. Researchers will need to determine precisely how SLK influences c-Myc: whether it phosphorylates c-Myc directly, modifies another component of the transcriptional machinery, changes chromatin accessibility or stabilizes a larger regulatory complex. It will also be important to establish whether SLK’s kinase activity is required, or whether the protein can function as a scaffold independent of catalysis. These distinctions matter because an enzymatic dependency may be targeted with a conventional small-molecule inhibitor, whereas a structural interaction could require a different approach, such as a molecular glue, targeted protein degrader or interface-disrupting compound. Future work will also have to clarify how broadly the cancer-specific effect applies and whether blocking the pathway can suppress tumors without triggering compensatory signaling.
For now, the study offers a vivid example of how looking at a cancer protein’s immediate molecular surroundings can uncover biology that remains invisible to standard interaction screens. By illuminating the proteins gathered around c-Myc in living cells, the researchers identified SLK as a potentially important co-regulator and exposed a connection that may be particularly valuable in malignant biology. The result does not make c-Myc an easy target, but it changes the question from how to shut down the transcription factor everywhere to how cancer cells uniquely depend on the machinery surrounding it. That shift could ultimately guide more selective treatments aimed at the support networks that tumors build around their most aggressive growth drivers.
Subject of Research: The cancer-specific molecular regulation of c-Myc and the role of SLK as a co-regulator identified through photoproximity labeling.
Article Title: Photoproximity labeling of c-Myc reveals SLK as a cancer-specific co-regulator.
Article References: Milione, R.R., Tong, F., Wolfe, K.L. et al. Photoproximity labeling of c-Myc reveals SLK as a cancer-specific co-regulator. Nature Chemical Biology (2026). https://doi.org/10.1038/s41589-026-02284-0
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s41589-026-02284-0
Keywords: c-Myc, SLK, cancer biology, photoproximity labeling, proximity proteomics, transcription factors, cancer-specific co-regulators, kinase signaling, molecular oncology, targeted therapy
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