Abstract 5296: DNAJA1 promotes cancer progression by stabilizing mutant p53

Abstract

Abstract The tumor suppressor p53 is mutated in approximately 50% of human cancers. Majority of them are missense mutations, which results in accumulation of dysfunctional p53 proteins in tumors. Increasing evidence suggests that accumulation of mutant p53 is crucial for its oncogenic gain-of-function activities, such as proliferation, metastasis, and chemotherapy resistance. Previous work from our lab has revealed that DNAJA1, a HSP40 family member, specifically binds to and stabilizes conformational/misfolded mutant p53. DNAJA1 downregulation induces ubiquitination and proteasomal degradation of conformational p53 mutants, but does not affect the levels of wild-type p53 or DNA contact mutants. Based on these observations, we hypothesize that DNAJA1 promotes cancer progression in a manner dependent on conformational/misfolded mutant p53. To test this hypothesis, we examined the effects of DNAJA1 deletion/knockdown on malignant properties of head and neck squamous cell carcinoma (HNSCC) cells. Genetic deletion/knockdown of DNAJA1 resulted in reduced proliferation, colony formation, migration, and orthotopic tumor growth of HNSCC cells expressing conformational mutant p53, but not DNA contact mutant p53. These cellular phenotypes induced by DNAJA1 knockdown/knockout were substantially rescued by overexpression of DNAJA1 or mutant p53. We also conducted RNA sequencing analyses using HN31 cells (control, DNAJA1 knockdown or mutant p53 knockdown). Notably, 77.2% of downregulated genes by p53 knockdown were overlapped with genes downregulated by DNAJA1 knockdown. Moreover, genes involved in cancer-related pathways, including adhesion and actin cytoskeleton organization, were commonly downregulated. These results strongly suggest that DNAJA1 promotes HNSCC progression mostly dependent on conformational mutant p53. Our results may also suggest that DNAJA1 could be a novel therapeutic target for cancers carrying conformational/misfolded mutant p53. Citation Format: Tomoo Iwakuma. DNAJA1 promotes cancer progression by stabilizing mutant p53 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5296.