Loss of ACSM3 confers worsened prognosis and immune exclusion to cutaneous melanoma

Zhu, Zhidong; Wang, Duoqin; Shen, Yanyun

doi:10.7150/jca.48354

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J Cancer 2020; 11(22):6582-6590. doi:10.7150/jca.48354 This issue Cite

Research Paper

Loss of ACSM3 confers worsened prognosis and immune exclusion to cutaneous melanoma

Zhidong Zhu¹, Duoqin Wang², Yanyun Shen^2✉

1. Department of Cardiology, Huashan Hospital, Fudan University, PR, China
2. Department of Dermatology, Huashan Hospital, Fudan University, PR, China
^#Equal contributor

Citation:

Zhu Z, Wang D, Shen Y. Loss of ACSM3 confers worsened prognosis and immune exclusion to cutaneous melanoma. J Cancer 2020; 11(22):6582-6590. doi:10.7150/jca.48354. https://www.jcancer.org/v11p6582.htm

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Abstract

Aim: Malignant melanoma (MM) is a highly aggressive cutaneous cancer with undetermined underlying genetic disposition. We aim to evaluate prognostic and mechanistic role of ACSM3 in MM.

Methods: In silico reproduction of TCGA MM dataset, GEO dataset, GDSC dataset and human protein atlas was performed to establish differential expression of ACSM3. In vitro and in vivo validation using A375 and SKMEL1 MM cells were performed to profile tumorigenic role and functional attribution of the gene.

Results: ACSM3 expression was significantly downregulated in MM. Lower expression of ACSM3 conferred worsened prognosis of MM. Lower ACSM3 was observed in Asian ethnicity. Knock-down (KD) and overexpression (OE) of ACSM3 resulted in significant increased and decreased proliferation, invasion and colony formation in MM cells, respectively. Pathway annotation revealed significantly active immune response invoked by ACSM3. Lower ACSM3 expression was associated with decreased CD8+, macrophage and dendritic cell infiltration. Cox regression revealed loss of survival contribution of ACSM3 in the presence of immune infiltrates supporting immune regulatory role of ACSM3. Drug sensitivity analysis revealed BRAF inhibitor PLX-4720 was sensitive in both MM cells. ACSM3 expression showed no correlation with immune checkpoint molecules. Combined ACSM3-OE and PLX-4720 in MM cells showed synergistic inhibition in MM cells and xenograft murine models with no significant toxicity.

Conclusion: Loss of ACSM3 was associated with poor prognosis in MM. Overexpression of ACSM3 synergistically inhibited MM with PLX-4720. ACSM3 was potentially associated with immune exclusion in MM. Further validation was warranted in future studies.

Keywords: Malignant melanoma, ACSM3, Cancer immunity

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APA

Zhu, Z., Wang, D., Shen, Y. (2020). Loss of ACSM3 confers worsened prognosis and immune exclusion to cutaneous melanoma. Journal of Cancer, 11(22), 6582-6590. https://doi.org/10.7150/jca.48354.

ACS

Zhu, Z.; Wang, D.; Shen, Y. Loss of ACSM3 confers worsened prognosis and immune exclusion to cutaneous melanoma. J. Cancer 2020, 11 (22), 6582-6590. DOI: 10.7150/jca.48354.

NLM

CSE

Zhu Z, Wang D, Shen Y. 2020. Loss of ACSM3 confers worsened prognosis and immune exclusion to cutaneous melanoma. J Cancer. 11(22):6582-6590.

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