Gobal crotonylome reveals that HNRNPC and its crotonylation promote p53-deficient tumor growth by stabilizing CCND1 and MCM3 mRNAs

Abstract

The role of p53 deficiency or mutation in regulating nonhistone protein crotonylation and its impact on cancer development remain unclear. The present study identified crotonylation as a therapeutic target in patients with p53 deficiency or mutation in colorectal cancer. Crotonylome analysis revealed that p53 deficiency upregulated heterogeneous nuclear ribonucleoprotein C (HNRNPC) and HNRNPC^K189Cr, promoting colorectal cancer cell proliferation by stabilizing CCND1 and MCM3 mRNAs through the MDM2/HDAC3 axis. Functional studies using HNRNPC^K189Q (activating mutation) and HNRNPC^K189R (inactivating mutation) confirmed the role of HNRNPC^K189Cr in tumor growth. HDAC3 was identified as a specific decrotonylase of HNRNPC^K189Cr. Sodium phytate, an HDAC3 agonist, effectively decrotonylated HNRNPC^K189Cr and, in combination with HNRNPC siRNA, significantly inhibited the in vitro and in vivo growth of HCT116 p53^−/− cells. An AOM/DSS-induced colorectal cancer model in K14-cre; p53 ^fl/fl mice validated the role of the p53/MDM2/HDAC3/HNRNPC^K189Cr axis in tumor progression. Additionally, the findings in the oral cancer cells WSU-HN6 and non-small lung cancer cells H1299 were in line with those in the HCT116 cells, suggesting that the p53/MDM2/HDAC3/HNRNPC^K189Cr regulatory mechanism plays a key role in a conserved manner. These findings revealed a novel mechanism by which p53 deficiency or mutation drives tumor progression via HNRNPC^K189Cr through MDM2/HDAC3 axis-mediated CCND1 and MCM3 mRNA stability. Targeting HNRNPC and its crotonylation with sodium phytate and HNRNPC siRNA offers a promising therapeutic strategy, potentially converting p53 from an “undruggable” target to a “druggable” target.