Acetylated DNMT1 Downregulation and Related Regulatory Factors Influence Metastatic Melanoma Patients Survival.

Publication Title

Cancers (Basel)

Authors

Xiaoqing Zhang, Department of Translational Molecular Medicine, John Wayne Cancer Institute (JWCI) at Providence Saint John's Health Center, Santa MonicaFollow
Matias A Bustos, Department of Translational Molecular Medicine, John Wayne Cancer Institute (JWCI) at Providence Saint John's Health Center, Santa MonicaFollow
Yoshiaki Shoji, Division of Molecular Oncology, Department of Translational Molecular Medicine, Saint John's Cancer Institute at Providence Saint John's Health Center, 2200 Santa Monica Blvd, Santa Monica, CA, 90404, USAFollow
Romela Irene Ramos, Department of Translational Molecular Medicine, Saint John's Cancer Institute (SJCI), Providence Saint John's Health Center (SJHC), Santa Monica, CA 90404, USA.Follow
Yuuki Iida, Department of Translational Molecular Medicine, Saint John's Cancer Institute (SJCI), Providence Saint John's Health Center (SJHC), Santa Monica, CA 90404, USA.
Rebecca Gross, Department of Translational Molecular Medicine, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA 90404, USA.Follow
Teh-Ling Takeshima, Department of Translational Molecular Medicine, Saint John's Cancer Institute (SJCI), Providence Saint John's Health Center (SJHC), Santa Monica, CA 90404, USA.Follow
Dave Hoon, Department of Translational Molecular Medicine, Saint John's Cancer Institute (SJCI), Providence Saint John's Health Center (SJHC), Santa Monica, CA 90404, USA.Follow

Document Type

Article

Publication Date

9-18-2021

Keywords

california; santa monica; jwci; sjci

Abstract

The role of post-translational modifications (PTM) of the key epigenetic factor DNMT1 protein has not been well explored in cutaneous metastatic melanoma progression. The acetylated DNMT1 (ac-DNMT1) protein level was assessed using an anti-acetylated lysine antibody in a clinically annotated melanoma patient tumor specimen cohort. In this study, we showed that surgically resected tumors have significantly higher DNMT1 protein expression in metastatic melanoma (stage III metastasis n = 17, p = 0.0009; stage IV metastasis n = 164, p = 0.003) compared to normal organ tissues (n = 19). Additionally, reduced ac-DNMT1 protein levels were associated with melanoma progression. There was a significant inverse correlation between ac-DNMT1 and DNMT1 protein levels in stage IV metastatic melanoma (r = -0.18, p = 0.02, n = 164). Additionally, ac-DNMT1 protein levels were also significantly positively correlated with TIP60 (r = 0.6, p < 0.0001) and USP7 (r = 0.74, p < 0.0001) protein levels in stage IV metastatic melanoma (n = 164). Protein analysis in metastatic melanoma tumor tissues showed that with high ac-DNMT1 (p = 0.006, n = 59), or concurrent high ac-DNMT1 with low DNMT1 (p = 0.05, n = 27), or high TIP60 (p = 0.007, n = 41), or high USP7 (p = 0.01, n = 48) consistently showed better 4-year melanoma-specific survival (MSS). Multivariate Cox proportional hazard analysis showed that ac-DNMT1 level is a significant independent factor associated with MSS (HR, 0.994; 95% confidential interval (CI), 0.990-0.998; p = 0.002). These results demonstrated that low ac-DNMT1 levels may represent an important regulatory factor in controlling metastatic melanoma progression and a promising factor for stratifying aggressive stage IV metastasis.

Area of Special Interest

Cancer

Specialty/Research Institute

Oncology