CD13 promotes hepatocellular carcinogenesis and sorafenib resistance by activating HDAC5‐LSD1‐NF‐κB oncogenic signaling

Abstract

Abstract Rationale CD13 is a new marker for liver cancer stem cells (CSCs) that contributes to sorafenib resistance in hepatocellular carcinoma (HCC). However, the underlying mechanism of CD13 in HCC sorafenib resistance remains enigmatic. Methods The expression of CD13 in HCC cell lines and tissues was assayed by RT‐PCR, western‐blot, and immunohistochemistry staining. Athymic BALB/c nu/nu mice model was used to study the in vivo functions of CD13. Clinical significance of CD13 was evaluated by Kaplan‐Meier methods. Cellular proliferation rate was evaluated by cell counting kit‐8 cell proliferation assay and colony formation assay. Tunel assay was used to detect cell death ratio. Transwell assay was used to evaluate the motility of cells. Immunoprecipitation (IP), liquid chromatography‐mass spectrometry (LC‐MS)/MS, and co‐IP were applied to investigate potential protein interactions of CD13. Results In this research, we found that CD13 expression was higher in metastatic HCC samples, and its overexpression was predicted worse prognosis for patients after surgical resection. Functionally, CD13 promoted HCC proliferation, invasion, cell cycle progression as well as sorafenib resistance. Mechanistically, CD13 interacted with histone deacetylase5 (HDAC5) to promote its protein stability, thus resulting in HDAC5‐mediated lysine‐specific demethylase 1 (LSD1) deacetylation and protein stabilization. Consequently, LSD1 decreased the NF‐κB catalytic unit p65 methylation that led to p65 protein stability. A CD13 inhibitor ubenimex in combination with sorafenib, suppressed the tumor growth and attenuated the resistance of HCC cells toward sorafenib in patient‐derived xenograft models. Conclusions CD13 promotes HCC progression and induces sorafenib resistance, mainly via interacting with HDAC5 to prevent the degradation of p65 and activate NF‐kB signaling pathway. CD13 is a prognostic indicator for HCC patients underwent curative resection as well as a predictor of response to treatment with sorafenib. Our study establishes the new therapeutic potential of targeting CD13‐HDAC5‐LSD1‐NF‐κB in HCC.

Keywords

• CD13
• HDAC5
• hepatocellular carcinoma
• patient derived tumor grafts
• sorafenib‐resistance