P53 inactivation occurs in about 50% of human cancers, where p53-driven p21 activity is devoid, and p27 becomes essential for establishing the G1/S checkpoint upon DNA damage. Here, we show that the E2F1-responsive lncRNA LIMp27 selectively represses p27 expression and contributes to proliferation, tumorigenicity, and treatment resistance in p53-defective colon adenocarcinoma (COAD) cells. Although LIMp27 was commonly upregulated in COAD tissues compared with normal colon tissues, high LIMp27 expression was only associated with poor overall survival (OS) of patients with tumors carrying mutant p53. In contrast, there was no significant relationship between LIMp27 expression and OS of patients with wildtype p53 tumors. Indeed, si/shRNA knockdown of LIMp27 diminished proliferation and tumorigenicity in mutant but not wildtype p53 COAD cells. Mechanistic investigations revealed that LIMp27 promoted p27 mRNA degradation through competitively binding to cytoplasmic hnRNPA0, which, upon DNA damage, translocated from the nucleus to the cytoplasm in p53-defective but not in wildtype p53 cancer cells where it otherwise interacts and stabilizes p27 mRNA. Significantly, the depletion of LIMp27 rendered mutant p53 COAD xenografts more sensitive to clinically available DNA-damaging chemotherapeutic drugs. Collectively, these results uncover a lncRNA mechanism that promotes p53-defective cancer pathogenesis and suggests that interference with LIMp27, alone or in combination with DNA-damaging therapeutics, represents a potential approach for the treatment of p53-defective cancers.