The LIN28/let-7 Pathway in Cancer

Abstract

Among all tumor suppressor microRNAs, reduced let-7 expression occurs most frequently in cancer and typically correlates with poor prognosis. Activation of either LIN28A or LIN28B, two highly related RNA binding proteins (RBPs) and proto-oncogenes, is responsible for the global post-transcriptional downregulation of the let-7 microRNA family observed in many cancers. Specifically, LIN28A binds the terminal loop of precursor let-7 and recruits the Terminal Uridylyl Transferase (TUTase) ZCCHC11 that polyuridylates pre-let-7, thereby blocking microRNA biogenesis and tumor suppressor function. For LIN28B, the precise mechanism responsible for let-7 inhibition remains controversial. Functionally, the decrease in let-7 microRNAs leads to overexpression of their oncogenic targets such as MYC, RAS, HMGA2, BLIMP1, among others. Furthermore, mouse models demonstrate that ectopic LIN28 expression is sufficient to drive and/or accelerate tumorigenesis via a let-7 dependent mechanism. In this review, the LIN28/let-7 pathway is discussed, emphasizing its role in tumorigenesis, cancer stem cell biology, metabolomics, metastasis, and resistance to ionizing radiation and several chemotherapies. Also, emerging evidence will be presented suggesting that molecular targeting of this pathway may provide therapeutic benefit in cancer.

Keywords: Lin28; cancer stem cells; let-7; microRNAs; proto-oncogene proteins.

Figure 1

Schematic of human LIN28A and LIN28B proteins. These highly related proto-oncogenes have two distinct RNA binding regions. The first is a cold-shock domain (highlighted in blue) with preference for GNGAY RNA sequences while the CCHC Zn fingers (highlighted in green) bind preferentially to a GRAG motif (R = G or A). Binding to both RNA sites is required for high affinity pre-let-7 binding. Putative nucleolar localization signal (NoLS) and nuclear localization signal (NLS) are reported for LIN28B.

Figure 2

Alignment of human pre-let-7 sequences (partial) with a focus on the terminal loop. The bases shown in red font are part of the let-7-5p/let-7-3p microRNA duplex following cytoplasmic Dicer cleavage. Black boxes and asterisks denote perfectly conserved bases while blue boxes represent bases where 10/12 are identical across all let-7 family members. Note that the GRAG (9 GGAG > 2 GAAG) motif is conserved across all family members except human let-7a-3 that is reported to escape LIN28AB-mediated repression. This RNA sequence motif is bound by the CCHC zinc fingers while the cold shock domain binds the GNGAY motif (and close variants) that lies at varying distances 5′ of the GGAG motif.

Figure 3

The LIN28AB/let-7 axis has significant biological functions. LIN28AB expression is high in undifferentiated cells where these proteins block biogenesis of the let-7 microRNA family. As differentiation progresses, LIN28AB expression is lost, resulting in production of mature let-7 microRNAs that themselves negatively regulate LIN28AB. During cellular transformation, wound healing (in particular in young mammals), and in the generation of iPSCs, LIN28AB helps drive pluripotency, self-renewal, de-differentiation, and/or cellular transformation.

Figure 4

The LIN28AB/let-7 axis has significant impact on cancer hallmarks. LIN28AB through let-7 dependent and independent mechanisms promote multiple processes that promote cancer development and progression.

Figure 5

Model for LIN28A/ZCCHC11 regulation of let-7 microRNA biogenesis, promoting cellular proliferation and modifying bioenergetics. LIN28A recruits the TUTase ZCCHC11 to pre-let-7 where ZCCHC11 adds a short polyU tail to pre-let-7. Pre-let-7 is no longer a DICER substrate and is targeted for degradation by DIS3L2, thereby blocking let-7 maturation into its functional tumor suppressor form. Loss of mature let-7 microRNAs causes overexpression of numerous oncogenes and bioenergetic genes.

Figure 6

Transcriptional networks that regulate LIN28B expression. LIN28B is highly expressed during embryogenesis and as differentiation progresses, LIN28B expression is lost. In adult mammals, only a small subset of somatic cells exist where LIN28B expression occurs. Several transcription factors such as MYC and NF-κB promote LIN28B transcription, while REST and ESE3/EHF are transcriptional repressors.