Deacetylation of ACLY Mediates RNA M6A‐Modification of NOXA and Promotes Chemoresistance of Colorectal Cancer

Abstract Chemoresistance is a major challenge for colorectal cancer (CRC) therapy and is a leading cause of cancer mortality, yet the underlying molecular mechanism remains unclear. ATP citrate lyase (ACLY), a rate‐limiting enzyme of de novo lipid synthesis, plays an important role in tumor progression and chemotherapy. Here, It is demonstrated that deacetylation of ACLY is critical for chemoresistance in CRC. Through proteomic screening acetylated proteins in chemoresistant patient‐derived cells, It is identified that ACLY is deacetylated at K978 site, which induces the relocation of ACLY to the nucleus and promotes its binding to RNA‐binding protein 15 (RBM15). This facilitates N 6 ‐methyladenosine (m 6 A) methylation of NOXA (also known as PMAIP1, phorbol‐12‐myristate‐13‐acetate‐induced protein 1) and decreases the stability of NOXA mRNA, resulting in chemoresistance. With the selective inhibitor Santacruzamate A, targeting the deacetylase histone deacetylase 2 (HDAC2) to inhibit the acetylation may enhance the sensitivity of chemoresistance. These findings provide new insights into the mechanism of ACLY deacetylation promoting chemoresistance and suggest a potential therapeutic strategy to mitigate the chemoresistant effects.