<p>Originally identified in the 1990s as an extracellular matrix (ECM) protein, Cellular Communication Network factor 3 (CCN3) was recognized as a member of a structurally related family of six proteins sharing a conserved tetramodular organization and broad regulatory functions in biological processes such as cell proliferation, attachment, migration, differentiation, wound healing, and angiogenesis, as well as in pathological conditions including fibrosis and tumorigenesis. Among these proteins, CCN3 rapidly emerged as the first tumor-suppressive member capable of negatively regulating cell growth in both normal and pathological contexts. A conceptual shift emerged following observations that, in addition to full-length CCN3 detected in the extracellular matrix, amino-truncated CCN3 proteoforms are targeted to the nucleus. In addition to physically interacting with the Rpb7 subunit of RNA polymerase II (Pol II), CCN3 binds to the promoter region of PAI-2 and exhibits transcriptional regulatory activity both in vitro and ex vivo. The dual localization and functional versatility of CCN3 led to the proposal that this protein may function as a “moonlighting” factor capable of integrating extracellular cues with nuclear transcriptional regulation. This conceptual framework, however, has remained relatively underexplored. The nuclear localization of other family members, together with the more recent observation that nuclear CCN6 physically interacts with RNA polymerase II, may extend this concept to the entire CCN protein family. By revisiting and integrating a substantial body of published data that has remained insufficiently acknowledged, this review aims to underscore the biological significance of CCN proteoforms in the nuclei of tumor cells. The demonstration of physical interactions between CCN3 and components of the central transcriptional machinery invites reconsideration of the prevailing ECM-centered view of CCN proteins and opens new perspectives on their biological roles.&#xa0;</p> Graphical Abstract <p>Panel A: Dual biological effects of CCN3. Expression of full-length CCN3 via pRSV-recombinant vectors in chicken embryo fibroblasts (CEF) leads to CCN3 secretion and marked inhibition of cell growth. The transforming potential of amino-truncated CCN3 species, originally observed in nephroblastoma, was reproduced ex vivo by infecting CEF with a pRSV vector carrying truncated CCN3 DNA cloned from the same tumor. Panel B: Combinatorial events of CCN3 modules. The secreted CCN3 proteins exhibit combinatorial biological activities through their constitutive modules. Each module can perform specific functions individually, or together they can generate new functions present in the full-length protein, highlighting the modular “whole in one” concept. Panel C: Pre-initiation Pol II complex. The 12-subunit RNA Pol II pre-initiation complex (PIC) includes a protruding rpb4/rpb7 heterodimer that stabilizes the complex and extends its capacity to interact with transcription factors. Two-hybrid assays suggest CCN3 physically contacts Pol II at this level. Binding of the CCN3 C-terminal (CT) domain to the PAI-2 promoter supports a role for CCN3 in regulating PIC progression and its interaction with TFIID/TBP family regulators. Panel D: CCN5 as a dominant regulator. Some transcription factors require dimerization to regulate target genes. CCN proteins, with CT and VWC domains, can dimerize or multimerize to modulate transcription positively or negatively. CCN5, which lacks the CT domain, may still dimerize thanks to the VWC domain, and could act as a dominant negative regulator when CT-mediated dimerization is essential for promoter binding and transcriptional regulation.</p> <p></p>