SPINDLIN1 antagonist: An emerging cancer drug class?

09 Apr 2021

Transcription factor has long been an attractive drug candidate for cancer drug development as it can potentially inhibit lineage-specific transcription.1,2 Recently, researchers from the University of Hong Kong reported a stable protein complex, Spindlin1, which binds stably to methylated histone and regulates ribosomal RNA synthesis. The interaction is the strongest binding ever reported, as evidenced by the multivalent methylated histone marks, and the protein complex Spindlin1 can be a potential target for cancer drug development.3

Cancer represents one of the major disease burden worldwide.4 Globally, more than 26 million new diagnosis of malignancy are expected by 2030, extrapolating to 17 million deaths per year.2 Transcription of ribosomal RNA (rRNA) is one of the key steps in protein synthesis and its dysregulation is responsible for survival of tumor cells.5-6 Specifically, transcription factors interact with co-factors to sustain rRNA machinery in order to support the fast growth rate of cancer cells.2 Recently, the transcription factor Spindlin1, which controls spindle organization and chromosomal stability, has been found to be upregulated in major malignancies including ovarian cancer and breast cancer.5-6 Experimental knockout of Spindlin1 abolished tumor cell proliferation.5 Likewise, in vitro inhibition of spindlin1  renders otherwise drug-resistant breast cancer cells sensitive to chemotherapeutic agents.6 In this connection, Spindlin1 has been investigated as a potential target for cancer drug development.2

Dr. Qian Chengmin, Associate Professor at the School of Biomedical Science, the University of Hong Kong, and his team reported a Spindlin1/C11orf84 protein complex which binds to the H3 histone protein with trimethylation signature on the 3rd and 9th lysine residues (H3K4me3K9me3).1 The interaction between Spindlin1 and C11orf84 was confirmed by co-immunoprecipitation and confocal microscopy.3 Binding of the Spindin1/C11orf84 protein complex to the dually-trimethylated histone protein H3 could displace heterochromatin protein 1 (HP1) from the H3K4me3K9me3-enriched rDNA loci.3 This in turn exposes the chromatin binding site for RNA polymerase I and initiates rRNA transcription and protein synthesis. Briefly, Spindlin1 has three Tudor domains in selective interactions with their effector proteins regulating the rRNA transcription. The research teams have also elucidated the crystal structure of the Sphindlin1 protein complex which could facilitate future development of specific antagonists.3

In multiple types of tumor cells, the expression of both Spindlin1 and C11orf84 is elevated.3,5 This overexpression in tumor cells is required to compensate the abnormally high cellular proliferation rate.3,5,6 Spindlin1 belongs to SPIN/SSTY gene family which confers the stability of chromatin and cellular spindle organization.5 The serine residues at positions 84 and 99 within Sphindlin1 protein are important in mediating the oncogenic properties through WNT/TCF-4 signalling. In this connection, experimental alteration of the expression level of Spindlin1 could effectively reduce tumor cell migration, invasion, promote apoptosis, and sensitize the malignant cells to chemotherapy.6 Modulation of Spindlin1 could be achieved indirectly by microRNA via the PI3K-Akt pathway.6

In summary, the novel finding of a stable interaction between Spindlin1 and the dually-trimethylated histone H3 protein could provide a druggable target for the future development of cancer therapeutic drugs.3 “Our study suggests a new therapeutic strategy of blocking Spindlin1 binding to methylated H3 to inhibit tumor growth and metastasis, concluded Dr. Chengmin and his colleagues.”3

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