Abstract LB245: TRIM29 mediates metastasis though hypoxia-regulated proteins in microsatellite-stable and p53-mutated colorectal cancers

Abstract

Abstract In the USA, colorectal cancer (CRC) is a leading cause of cancer deaths in men and women. Two primary molecular subtypes of CRCs are those with microsatellite instability (MSI) and those that are microsatellite stable (MSS). MSI-CRCs have a dysfunction of the mismatch repair (MMR) genes and are less aggressive; MSS-CRCs have active mismatch repair genes, account for 85% of sporadic CRCs, and are more aggressive. CRCs with MSI have a favorable prognosis and are candidates for immunotherapy; those with MSS have a poor prognosis and are resistant to various therapies. Our previous gene expression profiling studies of CRCs showed an association of high expression of tripartite motif-containing 29 (TRIM29) with MSS and p53 mutations. TRIM29, also known as ataxia telangiectasia group D-complementing (ATDC) protein, binds to p53 and inhibits its function. Since point mutations of p53 occur in 50% of CRCs and are associated with the MSS phenotype and with aggressiveness of CRCs, we assessed TRIM29 expression in CRC cells exhibiting various microsatellite and p53 status. With RNA sequencing and qPCR validation, we found higher expression of TRIM29 in MSS and p53-mutated types of CRC cells (HT29 and SW480) as compared to cells exhibiting MSI and the p53 wild-type (HCT116, LOVO, RKO and LS174T) as well as cells with MSS and the p53 wild-type (T84). TRIM29 knockdown studies with HT29 and SW480 CRC cells showed that TRIM29 contributes to the aggressive progression of cells with MSS and p53 mutations. Preclinical studies with experimental animals demonstrated that MSS and p53-mutated CRC cells (HT29) with high expression of TRIM29 metastasized more extensively to liver and bone relative to cells with stably inhibited TRIM29. Further, gene expression profiling of stably inhibited TRIM29 cells showed downregulation of P4HA1, ALDOC, and hexokinase2, enzymes that are involved in the hypoxia pathway. In summary, the present studies show that overexpression of TRIM29 contributes to CRC proliferation, invasion, migration, tumor growth, and experimental metastasis. Thus, targeting of TRIM29 with small molecule inhibitors could be an effective strategy for treatment of CRCs with MSS and p53 mutations. This work was supported in part by an NIH grant (3U54CA118948) and by a grant from the ELKUS foundation. Citation Format: Sumit Agarwal, Michael Behring, Prachi Bajpai, Amr Elkohly, Hyung-Gyoon Kim, Darshan S. Chandrashekar, Nirzari Gupta, Sameer Al Diffalha, Sooryanarayana Varambally, Upender Manne. TRIM29 mediates metastasis though hypoxia-regulated proteins in microsatellite-stable and p53-mutated colorectal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB245.