Here, we report the identification of p65BK, a novel BTK isoform, and show that it is expressed in colon cancers and that its expression is regulated by its 5′-untranslated region (UTR) via mitogen-activated protein kinase (MAPK)/heterogeneous nuclear ribonucleoprotein K (hnRNPK)-dependent and internal ribosome entry site (IRES)-driven translation of an alternatively spliced mRNA. Here, BTK is linked to malignant colon neoplasm.