PADI3 induces cell cycle arrest via the Sirt2/AKT/p21 pathway and acts as a tumor suppressor gene in colon cancer

Xiaotian Chang, Zhengbin Chai, Jiaorui Zou, et al.

Abstract


Objective: As a member of the peptidyl arginine deiminase (PAD) family, PADI3 is weakly expressed in colon cancer tissues andhighly expressed in adjacent colon cancer tissues. However, the role of PADI3 in colon cancer is unclear. In this study, weinvestigated the function and molecular mechanism of PADI3 in colon cancer tumorigenesis.

Methods: Western blot and real-time PCR were used to detect the expression levels of several genes. CCK-8, flow cytometry(FCM) and colony formation assays were used to examine cell proliferation, the cell cycle and colony formation ability. RNAsequencinganalysis was used to study the molecular mechanism of PADI3 in tumorigenesis. A truncation mutation experimentwas performed to determine the key functional domain of PADI3.

Results: PADI3 overexpression inhibited cell proliferation and colony formation and led to G1 phase arrest in both HCT116(originating from primary colon cancer) and LoVo (originating from metastatic tumor nodules of colon cancer) cells. PADI3-expressing HCT116 cells had a lower tumor formation rate and produced smaller tumors than control cells. PADI3 significantlydecreased Sirtuin2 (Sirt2) and Snail expression and AKT phosphorylation and increased p21 expression, and Sirt2 overexpressionpartly reversed the effects induced by PADI3 overexpression. Immunocytochemistry showed that PADI3 is mainly localized in thecytoplasm. Truncation mutation experiments showed that the C-domain is the key domain involved in the antitumor activityof PADI3.

Conclusions: PADI3 suppresses Snail expression and AKT phosphorylation and promotes p21 expression by downregulatingSirt2 expression in the cytoplasm, and the C-domain is the key domain for its antitumor activity.

Cite this article as: Chang X, Chai Z, Zou J, Wang H, Wang Y, Zheng Y, et al.PADI3 induces cell cycle arrest via the Sirt2/AKT/p21 pathway and acts as atumor suppressor gene in colon cancer. Cancer Biol Med. 2019; 16: 729-42.doi: 10.20892/j.issn.2095-3941.2019.0065


Keywords


PADI3; Sirt2; colon cancer; cell cycle; C-domain

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