PIM protein kinases regulate the level of the long noncoding RNA H19 to control stem cell gene transcription and modulate tumor growth

Abstract

The proviral integration site for Moloney murine leukemia virus (PIM) serine/threonine kinases have an oncogenic and prosurvival role in hematological and solid cancers. However, the mechanism by which these kinases drive tumor growth has not been completely elucidated. To determine the genes controlled by these protein kinases, we carried out a microarray analysis in T‐cell acute lymphoblastic leukemia (T‐ALL) comparing early progenitor (ETP‐ALL) cell lines whose growth is driven by PIM kinases to more mature T‐ALL cells that have low PIM levels. This analysis demonstrated that the long noncoding RNA (lncRNA) H19 was associated with increased PIM levels in ETP‐ALL. Overexpression or knockdown of PIM in these T‐ALL cell lines controlled the level of H19 and regulated the methylation of the H19 promoter, suggesting a mechanism by which PIM controls H19 transcription. In these T‐ALL cells, the expression of PIM1 induced stem cell gene expression (SOX2, OCT‐4, and NANOG) through H19. Identical results were found in prostate cancer (PCa) cell lines where PIM kinases drive cancer growth, and both H19 and stem cell gene levels. Small molecule pan‐PIM inhibitors (PIM‐i) currently in clinical trials reduced H19 expression in both of these tumor types. Importantly, the knockdown of H19 blocked the ability of PIM to induce stem cell genes in T‐ALL cells, suggesting a novel signal transduction cascade. In PCa, increases in SOX2 levels have been shown to cause both resistance to the androgen deprivation therapy (ADT) and the induction of neuroendocrine PCa, a highly metastatic form of this disease. Treatment of PCa cells with a small molecule pan‐PIM‐i reduced stem cell gene transcription and enhanced ADT, while overexpression of H19 suppressed the ability of pan‐PIM‐i to regulate hormone blockade. Together, these results demonstrate that the PIM kinases control the level of lncRNA H19, which in turn modifies stem cell gene transcription regulating tumor growth.

High Expression of NEK2 and PIM1, but Not PIM3, Is Linked to an Aggressive Phenotype of Bronchopulmonary Neuroendocrine Neoplasms

“…Moreover, increased PIM1 levels were associated with worse prognosis [ 41 ] and poorer response to chemotherapy in these tumors [ 42 ]. PIM1 was also showed to promote highly aggressive, neuroendocrine variant of prostate cancer by epigenetic changes in H19, suggesting it may be implicated in malignant neuroendocrine transformation [ 13 ]. Our study for the first time indicated that PIM1 mRNA expression is significantly higher in SCLC samples than in other BP-NEN entities.…”

“…Protein kinases regulate many cellular signaling pathways, and their disruption is often associated with carcinogenesis [9]. Although dysregulations of the NEK2, PIM1, and PIM3 kinase signaling axes have been implicated in the pathogenesis of several cancers [10,11], including those with a neuroendocrine phenotype [12,13], their role in the pathogenesis of BP-NENs has not been determined.…”

“…PIM1 is mainly expressed in the thymus, spleen, bone marrow, fetal liver, and other hematopoietic organs, while its expression is absent in adult tissues [11,20]. Abnormal expression of PIM1 has been linked to hematological malignancies [20,21], colon [22], bladder [23], head and neck squamous cell carcinoma [24], and prostate cancer [25,26], including the neuroendocrine variant: one of its most aggressive forms [13].…”

Propagation and Maintenance of Cancer Stem Cells: A Major Influence of the Long Non-Coding RNA H19

“…The long non-coding RNA H19 also participates to the maintenance of the CSC pool. For instance, microarray analysis showed an increased expression of H19 and the pluripotent transcriptional factors Sox2, Oct4, and Nanog in the bulk acute lymphoblastic leukemia cells compared to early progenitors [66]. In addition, our team recently highlighted a stem cell gene signature (Aldh1a1+; CD44+/CD24−) in breast tumors expressing higher H19.…”

“…Furthermore, links between H19, CSCs, and drug resistance have also been established. In prostate CSCs, H19 expression has been shown to promote both resistance to the androgen deprivation therapy (ADT) and the induction of highly metastatic form of prostate cancer [66]. In glioblastoma, knockdown of H19 expression leads to decreased cellular proliferation and a higher apoptotic rate after induction by chemotherapy (temozolomide).…”