Mechanistic link between long noncoding RNA and stability of oncogene reveals stemness and chemoresistance of hepatocellular carcinoma

Abstract

This letter comments on the recently published manuscript by Yu et al, in which the authors revealed a novel mechanism by which the m6A-modified long noncoding RNA kinesin family member 9-antisense RNA 1 promotes stemness and sorafenib resistance of hepatocellular carcinoma (HCC) through ubiquitin-specific peptidase 1-mediated deubiquitination of oncogene short stature homeobox 2. Given the high mortality rate and poor prognosis of HCC, the findings by Yu et al open a new avenue for overcoming HCC burden by focusing on kinesin family member 9-antisense RNA 1 and short stature homeobox 2 as prognostic markers and therapeutic targets.

Key Words: Kinesin family member 9-antisense RNA 1; Hepatocellular carcinoma; Ubiquitin-specific peptidase 1; Short stature homeobox 2; Chemoresistance

Core Tip: Hepatocellular carcinoma (HCC) is a type of highly aggressive tumor with poor prognosis. Therefore, a deeper understanding of molecular mechanism underlying HCC recurrence is crucial to effective treatment of HCC patients. This letter comments recent findings that the m6A-modified long noncoding RNA kinesin family member 9-antisense RNA 1 promotes stemness and sorafenib resistance of HCC through ubiquitin-specific peptidase 1-mediated deubiquitination of oncogene short stature homeobox 2, and we propose that kinesin family member 9-antisense RNA 1 and oncogene short stature homeobox 2 are potential prognostic markers and therapeutic targets of HCC.

TO THE EDITOR

Hepatocellular carcinoma (HCC) is one of the most highly aggressive cancers and remains a huge burden worldwide, especially in China with populations at high risk of HCC[1]. Because of aggressive progression of HCC, patients usually have poor prognosis due to recurrence and metastasis after surgery therapy such as hepatectomy, chemotherapy, or even recently proposed immunotherapy[2,3]. Therefore, a deeper understanding of molecular mechanism underlying HCC recurrence is crucial to effective treatment of HCC patients. Accumulating evidence has suggested that the interplay between tumor microenvironment and cancer stem cells plays an important role in metastasis and chemoresistance of HCC[4]. Cancer stem cells are driving force of HCC angiogenesis, metastasis and resistance to chemotherapy and radiotherapy[5,6]. In particular, genes involved in the regulation of stemness of HCC have been shown to be associated with prognosis in HCC patients[7]. In this context, a study recently published provided novel insight into the mechanism underlying the stemness and sorafenib resistance of HCC[8].

Main findings of this study

First, the authors showed that kinesin family member 9-antisense RNA 1 (KIF9-AS1) was highly expressed in HCC patients and KIF9-AS1 expression level was correlated with poor prognosis. Since methyltransferase like 3 (METTL3) is an m6A writer and m6A modification of long noncoding RNA (lncRNA) could increase the stability and expression of lncRNA, the authors examined the expression of METTL3 in HCC cells. As expected, METTL3 expression was high in HCC cells and silencing of METTL3 decreased m6A modification and stability/expression of KIF9-AS1 in HCC cells. Next, the authors explored the mechanism downstream of METTL3/KIF9-AS1. Interestingly, they found that KIF9-AS1 promoted the stability/expression of oncogene short stature homeobox 2 (SHOX2) via the upregulation of ubiquitin-specific peptidase 1 (USP1). While SHOX2 is subjected to ubiquitination medicated degradation, USP1 enhances the deubiquitination of SHOX2, leading to high level of SHOX2 in HCC cells. Consequently, SHOX2 promoted the stemness and sorafenib resistance of HCC cells. Furthermore, the authors explored the mechanism by which METTL3/KIF9-AS1/SHOX2 axis regulates HCC chemoresistance by the use of a xenograft model of HCC in mice. Taken together, these results suggest that m6A-modified KIF9-AS1 promotes HCC chemoresistance via the deubiquitination of SHOX2 mediated by USP1.

The limitations of this study and future directions

While the authors reveal a novel mechanistic link between lncRNA and the stability of oncogene to regulate HCC stemness and chemoresistance, which may have significance for the research of other types of cancers, this study has several limitations. First, it is unclear how KIF9-AS1 promotes USP1 upregulation. Future studies are needed to elucidate the underlying signaling mechanism[9,10]. Second, the authors should examine the correlation of METTL3, KIF9-AS1, USP1 and SHOX2 expression in HCC clinical samples, and their relationship with prognosis of HCC patients to establish novel prognostic model for HCC[11]. These data will provide important support for utilizing KIF9-AS1 and SHOX2 as prognostic markers and therapeutic targets of HCC.

Conclusion

In conclusion, this study has important significance for basic cancer research by linking the stability of lncRNA with the stability of oncogene in HCC progression and metastasis, and provides new directions for translational cancer research by focusing on KIF9-AS1 and SHOX2 as prognostic markers and therapeutic targets.