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Heterogeneous nuclear ribonucleoprotein L‐like ( HNRNPLL ), an  RNA ‐binding protein that regulates alternative splicing of pre‐ mRNA , has been shown to regulate differentiation of lymphocytes, as well as metastasis of colorectal cancer cells. Here, we show that  HNRNPLL  promotes cell cycle progression and, hence, proliferation of colorectal cancer cells. Functional annotation analysis of those genes whose expression levels were changed threefold or more in  RNA  sequencing analysis between  SW 480 cells overexpressing   HNRNPLL   and those knocked down for   HNRNPLL   revealed enrichment of  DNA  replication‐related genes by   HNRNPLL   overexpression. Among 13 genes detected in the  DNA  replication pathway,   PCNA  ,   RFC 3  and   FEN 1  showed reproducible upregulation by   HNRNPLL   overexpression both at  mRNA  and at protein levels in  SW 480 and  HT 29 cells. Importantly, knockdown of any of these genes alone suppressed the proliferation‐promoting effect induced by   HNRNPLL   overexpression.  RNA ‐immunoprecipitation assay presented a binding of  FLAG ‐tagged  HNRNPLL  to  mRNA  of these genes, and   HNRNPLL   overexpression significantly suppressed the downregulation of these genes during 12 h of actinomycin D treatment, suggesting a role of  HNRNPLL  in  mRNA  stability. Finally, analysis of a public  RNA  sequencing dataset of clinical samples suggested a link between overexpression of   HNRNPLL   and that of   PCNA  ,   RFC 3  and   FEN 1 . This link was further supported by immunohistochemistry of colorectal cancer clinical samples, whereas expression of  CDKN 1A, which is known to inhibit the cooperative function of  PCNA ,  RFC 3 and  FEN 1, was negatively associated with  HNRNPLL  expression. These results indicate that  HNRNPLL  stabilizes  mRNA  encoding regulators of  DNA  replication and promotes colorectal cancer cell proliferation.

HNRNPLL stabilizes mRNA for DNA replication proteins and promotes cell cycle progression in colorectal cancer cells